Bicyclic urea, thiourea, guanidine and cyanoguanidine compounds useful for the treatment of pain

ABSTRACT

or stereoisomers, tautomers, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein Ring A, Ring C and X are as defined herein, are inhibitors of TrkA kinase and are useful in the treatment of diseases which can be treated with a TrkA kinase inhibitor such as pain, cancer, inflammation/inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren&#39;s syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis and pelvic pain syndrome.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.14/442,609, filed May 13, 2015, which is a 35 U.S.C. § 371 applicationof International Application No. PCT/US2013/069951, filed Nov. 13, 2013,which claims the benefit of priority to U.S. Provisional Application No.61/725,925, filed Nov. 13, 2012. The entire content of the applicationsreferenced above are hereby incorporated by reference herein.

BACKGROUND OF THE INVENTION

The present invention relates to novel compounds, to pharmaceuticalcompositions comprising the compounds, to processes for making thecompounds and to the use of the compounds in therapy. More particularly,it relates to bicyclic urea, thiourea, guanidine and cyanoguanidinecompounds which exhibit TrkA kinase inhibition and which are useful inthe treatment of pain, cancer, inflammation/inflammatory diseases,neurodegenerative diseases, certain infectious diseases, Sjogren'ssyndrome, endometriosis, diabetic peripheral neuropathy, prostatitis andpelvic pain syndrome.

The current treatment regimens for pain conditions utilize severalclasses of compounds. The opioids (such as morphine) have severaldrawbacks including emetic, constipatory and negative respiratoryeffects, as well as the potential for addictions. Non-steroidalanti-inflammatory analgesics (NSAIDs, such as COX-1 or COX-2 types) alsohave drawbacks including insufficient efficacy in treating severe pain.In addition, COX-1 inhibitors can cause ulcers of the mucosa.Accordingly, there is a continuing need for new and more effectivetreatments for the relief of pain, especially chronic pain.

Trk's are the high affinity receptor tyrosine kinases activated by agroup of soluble growth factors called neurotrophins (NT). The Trkreceptor family has three members: TrkA, TrkB and TrkC. Among theneurotrophins are (i) nerve growth factor (NGF) which activates TrkA,(ii) brain-derived neurotrophic factor (BDNF) and NT-4/5 which activateTrkB and (iii) NT3 which activates TrkC. Trk's are widely expressed inneuronal tissue and are implicated in the maintenance, signaling andsurvival of neuronal cells (Patapoutian, A. et al., Current Opinion inNeurobiology, 2001, 11, 272-280).

Inhibitors of the Trk/neurotrophin pathway have been demonstrated to beeffective in numerous pre-clinical animal models of pain. For example,antagonistic NGF and TrkA antibodies such as RN-624 have been shown tobe efficacious in inflammatory and neuropathic pain animal models(Woolf, C. J. et al. (1994) Neuroscience 62, 327-331; Zahn, P. K. et al.(2004) J. Pain 5, 157-163; McMahon, S. B. et al., (1995) Nat. Med. 1,774-780; Ma, Q. P. and Woolf, C. J. (1997) NeuroReport 8, 807-810;Shelton, D. L. et al. (2005) Pain 116, 8-16; Delafoy, L. et al. (2003)Pain 105, 489-497; Lamb, K. et al. (2003) Neurogastroenterol. Motil. 15,355-361; Jaggar, S. I. et al. (1999) Br. J. Anaesth. 83, 442-448) andneuropathic pain animal models (Ramer, M. S. and Bisby, M. A. (1999)Eur. J. Neurosci. 11, 837-846; Ro, L. S. et al. (1999); Herzberg, U. etal., Pain 79, 265-274 (1997) Neuroreport 8, 1613-1618; Theodosiou, M. etal. (1999) Pain 81, 245-255; Li, L. et al. (2003) Mol. Cell. Neurosci.23, 232-250; Gwak, Y. S. et al. (2003) Neurosci. Lett. 336, 117-120).

It has also been shown that NGF secreted by tumor cells and tumorinvading macrophages directly stimulates TrkA located on peripheral painfibers. Using various tumor models in both mice and rats, it wasdemonstrated that neutralizing NGF with a monoclonal antibody inhibitscancer related pain to a degree similar or superior to the highesttolerated dose of morphine. Because TrkA kinase may serve as a mediatorof NGF driven biological responses, inhibitors of TrkA and/or other Trkkinases may provide an effective treatment for chronic pain states.

Recent literature has also shown that overexpression, activation,amplification and/or mutation of Trk kinases are associated with manycancers including neuroblastoma (Brodeur, G. M., Nat. Rev. Cancer 2003,3, 203-216), ovarian (Davidson. B., et al., Clin. Cancer Res. 2003, 9,2248-2259), colorectal cancer (Bardelli, A., Science 2003, 300, 949),melanoma (Truzzi, F., et al., Dermato-Endocrinology 2008, 3 (1), pp.32-36), head and neck cancer (Yilmaz, T., et al., Cancer Biology andTherapy 2010, 10 (6), pp. 644-653), gastric carcinoma (Du, J. et al.,World Journal of Gastroenterology 2003, 9 (7), pp. 1431-1434), lungcarcinoma (Ricci A., et al., American Journal of Respiratory Cell andMolecular Biology 25 (4), pp. 439-446), breast cancer (Jin, W., et al.,Carcinogenesis 2010, 31 (11), pp. 1939-1947), Glioblastoma (Wadhwa, S.,et al., Journal of Biosciences 2003, 28 (2), pp. 181-188),medulloblastoma (Gruber-Olipitz, M., et al., Journal of ProteomeResearch 2008, 7 (5), pp. 1932-1944), secratory breast cancer (Euthus,D. M., et al., Cancer Cell 2002, 2 (5), pp. 347-348), salivary glandcancer (Li, Y.-G., et al., Chinese Journal of Cancer Prevention andTreatment 2009, 16 (6), pp. 428-430), papillary thyroid carcinoma(Greco, A., et al., Molecular and Cellular Endocrinology 2010, 321 (1),pp. 44-49) and adult myeloid leukemia (Eguchi, M., et al., Blood 1999,93 (4), pp. 1355-1363). In preclinical models of cancer, non-selectivesmall molecule inhibitors of TrkA, B and C were efficacious in bothinhibiting tumor growth and stopping tumor metastasis (Nakagawara, A.(2001) Cancer Letters 169:107-114; Meyer, J. et al. (2007) Leukemia,1-10; Pierottia, M. A. and Greco A., (2006) Cancer Letters 232:90-98;Eric Adriaenssens, E., et al. Cancer Res (2008) 68:(2) 346-351).

In addition, inhibition of the neurotrophin/Trk pathway has been shownto be effective in treatment of pre-clinical models of inflammatorydiseases with NGF antibodies or non-selective small molecule inhibitorsof TrkA. For example, inhibition of the neurotrophin/Trk pathway hasbeen implicated in preclinical models of inflammatory lung diseasesincluding asthma (Freund-Michel, V; Frossard, N., Pharmacology &Therapeutics (2008) 117(1), 52-76), interstitial cystitis (Hu Vivian Y;et. al. The Journal of Urology (2005), 173(3), 1016-21), bladder painsyndrome (Liu, H.-T., et al., (2010) BJU International, 106 (11), pp.1681-1685), inflammatory bowel diseases including ulcerative colitis andCrohn's disease (Di Mola, F. F, et. al., Gut (2000) 46(5), 670-678) andinflammatory skin diseases such as atopic dermatitis (Dou, Y.-C., et.al. Archives of Dermatological Research (2006) 298(1), 31-37), eczemaand psoriasis (Raychaudhuri, S. P., et al., J Investigative Dermatology(2004) 122(3), 812-819).

The TrkA receptor is also thought to be critical to the disease processof the parasitic infection of Trypanosoma cruzi (Chagas disease) inhuman hosts (de Melo-Jorge, M. et al., Cell Host & Microbe (2007) 1(4),251-261).

Trk inhibitors may also find use in treating disease related to animbalance of the regulation of bone remodeling, such as osteoporosis,rheumatoid arthritis, and bone metastases. Bone metastases are afrequent complication of cancer, occurring in up to 70 percent ofpatients with advanced breast or prostate cancer and in approximately 15to 30 percent of patients with carcinoma of the lung, colon, stomach,bladder, uterus, rectum, thyroid, or kidney. Osteolytic metastases cancause severe pain, pathologic fractures, life-threatening hypercalcemia,spinal cord compression, and other nerve-compression syndromes. Forthese reasons, bone metastasis is a serious and costly complication ofcancer. Therefore, agents that can induce apoptosis of proliferatingosteoblasts would be highly advantageous. Expression of TrkA receptorshas been observed in the bone-forming area in mouse models of bonefracture (K. Asaumi, et al., Bone (2000) 26(6) 625-633). In addition,localization of NGF was observed in almost all bone-forming cells (K.Asaumi, et al.). Recently, it was demonstrated that a Trk inhibitorinhibits the signaling activated by neurotrophins binding to all threeof the Trk receptors in human hFOB osteoblasts (J. Pinski, et al.,(2002) 62, 986-989). These data support the rationale for the use of Trkinhibitors for the treatment of bone remodeling diseases, such as bonemetastases in cancer patients.

Trk inhibitors may also find use in treating diseases and disorders suchas Sjogren's syndrome (Fauchais, A. L., et al., (2009) ScandinavianJournal of Rheumatology, 38(1), pp. 50-57), endometriosis (Barcena DeArellano, M. L., et al., (2011) Reproductive Sciences, 18(12), pp.1202-1210; Barcena De Arellano, et al., (2011) Fertility and Sterility,95(3), pp. 1123-1126; Cattaneo, A., (2010) Current Opinion in MolecularTherapeutics, 12(1), pp. 94-106), diabetic peripheral neuropathy (Kim,H. C., et al., (2009) Diabetic Medicine, 26 (12), pp. 1228-1234;Siniscalco, D., et al., (2011) Current Neuropharmacology, 9(4), pp.523-529; Ossipov, M. H., (2011) Current Pain and Headache Reports,15(3), pp. 185-192), and prostatitis and pelvic pain syndrome (Watanabe,T., et al., (2011) BJU International, 108(2), pp. 248-251; and Miller,L. J., et al., (2002) Urology, 59(4), pp. 603-608).

Several classes of small molecule inhibitors of Trk kinases said to beuseful for treating pain or cancer are known (Expert Opin. Ther. Patents(2009) 19(3), 305-319).

SUMMARY OF THE INVENTION

It has now been found that pyrrolidinyl urea, thiourea, guanidine andcyanoguanidine compounds are inhibitors of TrkA, and useful for treatingdisorders and diseases such as pain, including chronic and acute pain.Compounds of the invention useful in the treatment of multiple types ofpain including inflammatory pain, neuropathic pain, and pain associatedwith cancer, surgery, or bone fracture. In addition, compounds of theinvention are useful for treating cancer, inflammation or inflammatorydiseases, neurodegenerative diseases, certain infectious diseases,Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy,prostatitis or pelvic pain syndrome, and diseases related to animbalance of the regulation of bone remodeling, such as osteoporosis,rheumatoid arthritis, and bone metastases.

Representative compounds of the invention (See Table B below), werefound to be highly selective for TrkA over a panel of about 230 otherkinases at 10 μM concentration. In addition, compounds of the inventionsuch as those shown in Table A below, were found to be at least 1000fold more selective for TrkA versus p38a.

More specifically, provided herein are compounds of Formula I:

or stereoisomers, tautomers, or pharmaceutically acceptable salts,solvates or prodrugs thereof, wherein Ring A, Ring C and X are asdefined herein.

Another aspect of the present invention provides methods of treating adisease or disorder modulated by TrkA, comprising administering to amammal in need of such treatment an effective amount of a compound ofthis invention or a stereoisomer, solvate or pharmaceutically acceptablesalt thereof. In one embodiment, the disease and disorders includechronic and acute pain, including but not limited to inflammatory pain,neuropathic pain, and pain associated with cancer, surgery, or bonefracture. In another embodiment, the disease and disorders include, butare not limited to, cancer, inflammation or inflammatory diseases,neurodegenerative diseases, certain infectious diseases, Sjogren'ssyndrome, endometriosis, diabetic peripheral neuropathy, prostatitis orpelvic pain syndrome, and diseases related to an imbalance of theregulation of bone remodeling, such as osteoporosis, rheumatoidarthritis, and bone metastases. In one embodiment, the treatmentincludes treating the mammal with a compound of this invention incombination with an additional therapeutic agent.

Another aspect of the present invention provides a pharmaceuticalcomposition comprising a compound of the present invention or apharmaceutically acceptable salt thereof.

Another aspect of the present invention provides the compounds of thepresent invention for use in therapy.

Another aspect of the present invention provides the compounds of thepresent invention for use in the treatment of disease and disorders suchas chronic and acute pain, including but not limited to inflammatorypain, neuropathic pain, and pain associated with cancer, surgery, orbone fracture. Another aspect of the present invention provides thecompounds of the present invention for use in the treatment of diseaseand disorders selected from cancer, inflammation or inflammatorydiseases, neurodegenerative diseases, certain infectious diseases,Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy,prostatitis or pelvic pain syndrome, and diseases related to animbalance of the regulation of bone remodeling, such as osteoporosis,rheumatoid arthritis, and bone metastases.

Another aspect of the present invention provides the use of a compoundof this invention in the manufacture of a medicament for the treatmentof disease and disorders such as chronic and acute pain including, butnot limited to, inflammatory pain, neuropathic pain, and pain associatedwith cancer, surgery, or bone fracture.

Another aspect of the present invention provides the use of a compoundof this invention in the manufacture of a medicament for the treatmentof disease and disorders selected from cancer, inflammation orinflammatory diseases, neurodegenerative diseases, certain infectiousdiseases, Sjogren's syndrome, endometriosis, diabetic peripheralneuropathy, prostatitis or pelvic pain syndrome, and diseases related toan imbalance of the regulation of bone remodeling, such as osteoporosis,rheumatoid arthritis, and bone metastases.

Another aspect of the present invention provides intermediates forpreparing compounds of Formula I.

Another aspect of the present invention includes methods of preparing,methods of separation, and methods of purification of the compounds ofthis invention.

DETAILED DESCRIPTION OF THE INVENTION

Provided herein are compounds, and pharmaceutical formulations thereof,that are potentially useful in the treatment of diseases, conditionsand/or disorders modulated by TrkA.

Representative compounds of the invention (See Table B below), werefound to be highly selective for TrkA over a panel of about 230 otherkinases at 10 M concentration. In addition, compounds of the inventionsuch as those shown in Table A below, were found to be at least 1000fold more selective for TrkA versus p38α.

One embodiment provides a compound of Formula I:

or stereoisomers, tautomers, or pharmaceutically acceptable salts,solvates or prodrugs thereof, wherein:

X is O, S, NH or N—CN;

Ring A is formula A-1 or A-2

Y is H, halogen, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkyl [optionallysubstituted with 1-5 fluoros], cyano(1-6C)alkyl, hydroxy(1-6C)alkyl,dihydroxy(2-6C)alkyl, aminocarbonyl(1-6C)alkyl, (1-6C)alkoxy [optionallysubstituted with 1-5 fluoros], CN, aminocarbonyl or (1-4Calkoxy)carbonyl;

R^(a), R^(b) and R^(c) are independently selected from H, halogen,(1-3C)alkyl, (1-3C)alkoxy and CN;

B is NR¹, O, a bond, CR^(d)R^(e), S or SO₂;

D is NR¹, O, a bond, CR^(f)R^(g), S or SO₂;

E is NR¹, O, a bond, CR^(h)R^(i), S or SO₂;

F is CR^(j)R^(k);

provided that the ring formed by B, D, E, and F together with the atomsto which they are attached contains at least five atoms and zero or oneof B, D or E is NR¹ or O;

G is CR^(m)R^(n);

K is NR^(l);

R¹ is (1-6C)alkyl [optionally substituted with one to five fluoros],(1-6C)cycloalkyl [optionally substituted with one to five fluoros],(1-3C alkoxy)(2-6C)alkyl [optionally substituted with one to fivefluoros], (1-6C)alkylC(═O)— or (1-6C alkoxy)C═O—;

R^(d), R^(e), R^(f), R^(g), R^(h), R^(i), R^(j) and R^(k) areindependently H, OH, (1-6C)alkyl [optionally substituted with one tofive fluoros], (3-6C)cycloalkyl [optionally substituted with one to fivefluoros], (1-3C alkoxy)(2-6C)alkyl [optionally substituted with one tofive fluoros], hydroxy(2-6C)alkyl [optionally substituted with one tofive fluoros], (2-6C)cyanoalkyl, (1-6C)alkoxy [optionally substitutedwith one to five fluoros], or (1-3C alkoxy)(2-6C)alkoxy [optionallysubstituted with one to five fluoros],

or one of a pair of R^(d) and R^(e), or R^(f) and R^(g), or R^(h) andR^(i), or R^(j) and R^(k), together with the carbon atom to which theyare attached form a (3-6C)cycloalkyl, oxetanyl or azetidinyl ring,

or one of a pair of R^(d) and R^(e), or R^(f) and R^(e), or R^(h) andR^(i), or R^(j) and R^(k) form an oxo group,

and wherein only one of R^(d) and R^(e) can be OH and neither is OH if Bis connected to a heteroatom, and only one of R^(f) and R^(g) can be OHand neither is OH if D is connected to a heteroatom, and only one ofR^(h) and R^(i) can be OH and neither is OH if E is connected to aheteroatom, and only one of R^(j) and R^(k) can be OH and neither is OHif F is connected to a heteroatom;

R^(m) is H, (1-3C)alkyl [optionally substituted with 1-5 fluoros],cyclopropyl or cyclobutyl, and

R^(n) is H or (1-3C)alkyl [optionally substituted with 1-5 fluoros], or

R^(m) and R^(n) together form an oxo group;

R^(p) is H, (1-6C)alkyl [optionally substituted with one to fivefluoros], (3-6C)cycloalkyl [optionally substituted with one to fivefluoros], (1-3C alkoxy)(2-6C)alkyl [optionally substituted with one tofive fluoros], hydroxy(2-6C)alkyl [optionally substituted with one tofive fluoros], or (2-6C)cyanoalkyl;

Ring C is formula C-1 or C-2

R³ is (1-6C)alkyl, hydroxy(1-6C)alkyl, Ar², hetCyc¹, (3-7C)cycloalkyl,or hetAr²;

Ar² is phenyl optionally substituted with one or more groupsindependently selected from halogen and (1-6C)alkyl;

hetCyc¹ is a 5-6-membered saturated or partially unsaturatedheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and 0;

hetAr² is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, O and S and optionally substituted withone or more groups independently selected from (1-6C)alkyl and halogen;

R⁴ is OH, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluro(2-6C)alkyl, pentafluro(2-6C)alkyl,cyano(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3Calkoxy)(1-6C)alkyl, amino(1-6C)alkyl, aminocarbonyl(1-6C)alkyl,(1-3C)alkylsulfonamido(1-6C)alkyl, sulfamido(1-6C)alkyl,hydroxycarbonyl(1-6C)alkyl, hetAr³(1-6C)alkyl, Ar³(1-6C)alkyl,(1-6C)alkoxy, monofluoro(1-6C)alkoxy, difluoro(1-6C)alkoxy,trifluoro(1-6C)alkoxy, tetrafluoro(2-6C)alkoxy, pentafluoro(2-6C)alkoxy,cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy,amino(2-6C)alkoxy, hydroxyl-carbonyl(1-6C)alkoxy, hetCyc²(1-6C)alkoxy,hetAr³(1-6C)alkoxy, Ar³(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (1-3Calkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl [optionally substitutedwith F, OH, (1-6C alkyl), (1-6C) alkoxy, or (1-3C alkoxy)(1-6C)alkyl],hetAr⁴, hetAr⁴—O—, Ar⁴, hetCyc²(O)CH₂—, (1-4Calkoxycarbonyl)(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy,aminocarbonyl(1-6C)alkoxy, hetCyc²C(═O)(1-6C)alkoxy, hydroxy(1-3Calkoxy)(1-6C)alkoxy, hydroxytrifluoro(1-6C)alkoxy,(1-3C)alkylsulfonamido(1-6C)alkoxy, (1-3C)alkylamido(1-6C)alkoxy,di(1-3C alkyl)amino-carboxy, hetCyc²C(═O)O—, hydroxydifluoro(1-6C)alkyl,(1-4C alkylcarboxy)(1-6C)alkyl, (1-6C)alkoxycarbonyl, hydroxylcarbonyl,aminocarbonyl, (1-3C alkoxy)aminocarbonyl, hetCyc³, halogen, CN,trifluoromethylsulfonyl, N-(1-3C alkyl)oxadiazolonyl, hetAr⁵ orhetCyc⁴-O—;

hetCyc² is a 4-6 membered heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O and optionally substituted with 1-2groups independently selected from (1-6C)alkyl, (1-4Calkylcarboxy)(1-6C)alkyl, and (1-6C)acyl;

hetCyc³ is a 4-7 membered heterocycle having 1-2 ring heteroatomsindependently selected from N and O and optionally substituted with oneor more substituents independently selected from F, CN, (1-6C)alkyl,trifluoro(1-6C)alkyl, hydroxy(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl,(1-6C)acyl-, (1-6C)alkylsulfonyl, trifluoromethylsulfonyl and (1-4Calkoxy)carbonyl;

hetAr³ is a 5-membered heteroaryl ring having 1-3 ring atomsindependently selected from N, O and S and optionally substituted with(1-6C)alkyl;

Ar³ is phenyl optionally substituted with (1-4C)alkoxy;

hetAr⁴ is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, S and O and optionally substituted withone or more substituents independently selected from (1-6C)alkyl,halogen, CN, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl,difluoro(1-6C)alkyl, fluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH₂— (3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6Calkyl)amino, (1-3C trifluoroalkoxy), fluoro(1-6C alkyl)amino,difluoro(1-6C alkyl)amino, trifluoro(1-6C alkyl)amino, and (3-4Ccycloalkyl)amino;

hetAr⁵ is a group selected from the structures:

where R^(z) is (3-4C)cycloalkyl or (1-3C)alkyl (optionally substitutedwith 1-3 fluoros), wherein each of said hetAr⁵ groups is optionallyfurther substituted with one or more groups independently selected fromF and (1-3C)alkyl optionally substituted with 1-3 fluoros;

hetCyc⁴ is a 7-8 membered bridged heterocycle having a ring nitrogenatom and optionally substituted with one or more groups independentlyselected from (1-6C)alkyl and halogen;

Ar⁴ is phenyl optionally substituted with one or more groupsindependently selected from (1-6C)alkyl, halogen, CN, CF₃, CF₃O—,(1-6C)alkoxy, (1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio,hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3Calkyl)OC(═O)—;

R⁵ is (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl,halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3C alkoxy)(1-4C)alkyl,(1-4C alkyl)OC(═O)—, (1-6C)alkylthio, (3-4C)cycloalkyl, amino,aminocarbonyl, trifluoro(1-3C alkyl)amido, or phenyl (optionallysubstituted with one or more groups independently selected from halogen,(1-6C)alkyl and (1-6C)alkoxy); or

R⁴ and R⁵ together with the atoms to which they are attached form a 5-6membered saturated, partially unsaturated or unsaturated carbocyclicring optionally substituted with one or more substituents independentlyselected from (1-6C)alkyl, or

R⁴ and R⁵ together with the atoms to which they are attached form 5-6membered saturated, partially unsaturated or unsaturated heterocyclicring having a ring heteroatom selected from N, O or S, wherein saidheterocyclic ring is optionally substituted with one or two substituentsindependently selected from (1-6C alkyl)C(═O)O—, (1-6C)acyl, (1-6C)alkyland oxo, and said sulfur ring atom is optionally oxidized to S(═O) orSO₂;

R^(3a) is hydrogen, halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl,(3-6C)cycloalkyl, phenyl optionally substituted with one or moresubstituents independently selected from halogen and (1-6C)alkyl, or a5-6 membered heteroaryl ring having 1-3 ring heteroatoms independentlyselected from N, O and S and optionally substituted with one or moregroups independently selected from (1-6C)alkyl and halogen;

R^(4a) is hydrogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, phenyl[optionally substituted with one or more groups independently selectedfrom (1-6C)alkyl, halogen, CN, CF₃, CF₃O—, (1-6C)alkoxy,(1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl,(1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3C alkyl)OC(═O)—], or a5-6 membered heteroaryl ring having 1-3 ring heteroatoms independentlyselected from N, S and O and optionally substituted with 1-2substituents independently selected from (1-6C)alkyl,hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH₂— (3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6Calkyl)amino and (1-3C trifluoroalkoxy)(1-3C)trifluoroalkyl; and

R^(5a) is hydrogen, halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl,(3-6C)cycloalkyl, phenyl optionally substituted with one or moresubstituents independently selected from halogen and (1-6C)alkyl, or a5-6 membered heteroaryl ring having 1-3 ring heteroatoms independentlyselected from N, O and S and optionally substituted with one or moregroups independently selected from (1-6C)alkyl and halogen.

In one embodiment compounds of Formula I include Formula I-1:

or stereoisomers, tautomers, or pharmaceutically acceptable salts, orsolvates or prodrugs thereof, wherein:

X is O, S, NH or N—CN;

Ring A is formula A-1 or A-2

Y is H, halogen, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkyl [optionallysubstituted with 1-5 fluoros], cyano(1-6C)alkyl, hydroxy(1-6C)alkyl,dihydroxy(2-6C)alkyl, aminocarbonyl(1-6C)alkyl, (1-6C)alkoxy [optionallysubstituted with 1-5 fluoros], or CN;

R^(a), R^(b) and R^(c) are independently selected from H, halogen,(1-3C)alkyl, (1-3C)alkoxy and CN;

B is NR¹, O, a bond, or CR^(d)R^(e);

D is NR¹, O, a bond, or CR^(f)R^(g);

E is NR¹, O, a bond, or CR^(h)R^(i);

F is CR^(j)R^(k);

provided that the ring formed by B, D, E, and F together with the atomsto which they are attached contains at least five atoms and zero or oneof B, D or E is NR¹ or O;

G is CR^(m)R^(n);

K is NR^(l);

R¹ is (1-6C)alkyl [optionally substituted with one to five fluoros],(1-6C)cycloalkyl [optionally substituted with one to five fluoros],(1-3C alkoxy)(2-6C)alkyl [optionally substituted with one to fivefluoros], (1-6C)alkylC(═O)— or (1-6C alkoxy)C═O—;

R^(d), R^(e), R^(f), R^(g), R^(h), R^(i), R^(j) and R^(k) areindependently H, OH, (1-6C)alkyl [optionally substituted with one tofive fluoros], (3-6C)cycloalkyl [optionally substituted with one to fivefluoros], (1-3C alkoxy)(2-6C)alkyl [optionally substituted with one tofive fluoros], hydroxy(2-6C)alkyl [optionally substituted with one tofive fluoros], or (2-6C)cyanoalkyl,

or one of a pair of R^(d) and R^(e), or R^(f) and R^(g), or R^(h) andR^(i), or R^(j) and R^(k), together with the carbon atom to which theyare attached form a (3-6C)cycloalkyl, oxetanyl or azetidinyl ring,

or one of a pair of R^(d) and R^(e), or R^(f) and R^(g), or R^(h) andR^(i), or R^(j) and R^(k) form an oxo group,

and wherein only one of R^(d) and R^(e) can be OH and neither is OH if Bis connected to a heteroatom, and only one of R^(f) and R^(g) can be OHand neither is OH if D is connected to a heteroatom, and only one ofR^(h) and R^(i) can be OH and neither is OH if E is connected to aheteroatom, and only one of R^(j) and R^(k) can be OH and neither is OHif F is connected to a heteroatom;

R^(m) is H, (1-3C)alkyl [optionally substituted with 1-5 fluoros],cyclopropyl or cyclobutyl, and

R^(n) is H or (1-3C)alkyl [optionally substituted with 1-5 fluoros], or

R^(m) and R^(n) together form an oxo group;

R^(p) is H, (1-6C)alkyl [optionally substituted with one to fivefluoros], (3-6C)cycloalkyl [optionally substituted with one to fivefluoros], (1-3C alkoxy)(2-6C)alkyl [optionally substituted with one tofive fluoros], hydroxy(2-6C)alkyl [optionally substituted with one tofive fluoros], or (2-6C)cyanoalkyl;

Ring C is formula C-1 or C-2

R³ is (1-6C)alkyl, hydroxy(1-6C)alkyl, Ar², hetCyc¹, (3-7C)cycloalkyl,or hetAr²;

Ar² is phenyl optionally substituted with one or more groupsindependently selected from halogen and (1-6C)alkyl;

hetCyc¹ is a 5-6-membered saturated or partially unsaturatedheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and 0;

hetAr² is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, O and S and optionally substituted withone or more groups independently selected from (1-6C)alkyl and halogen;

R⁴ is OH, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluro(2-6C)alkyl, pentafluro(2-6C)alkyl,cyano(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3Calkoxy)(1-6C)alkyl, amino(1-6C)alkyl, aminocarbonyl(1-6C)alkyl,(1-3C)alkylsulfonamido(1-6C)alkyl, sulfamido(1-6C)alkyl,hydroxycarbonyl(1-6C)alkyl, hetAr³(1-6C)alkyl, Ar³(1-6C)alkyl,(1-6C)alkoxy, monofluoro(1-6C)alkoxy, difluoro(1-6C)alkoxy,trifluoro(1-6C)alkoxy, tetrafluoro(2-6C)alkoxy, pentafluoro(2-6C)alkoxy,cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy,amino(2-6C)alkoxy, hydroxyl-carbonyl(1-6C)alkoxy, hetCyc²(1-6C)alkoxy,hetAr³(1-6C)alkoxy, Ar³(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (1-3Calkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl [optionally substitutedwith F, OH, (1-6C alkyl), (1-6C) alkoxy, or (1-3C alkoxy)(1-6C)alkyl],hetAr⁴, hetAr⁴—O—, Ar⁴, hetCyc²(O)CH₂—, (1-4Calkoxycarbonyl)(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy,aminocarbonyl(1-6C)alkoxy, hetCyc²C(═O)(1-6C)alkoxy, hydroxy(1-3Calkoxy)(1-6C)alkoxy, hydroxytrifluoro(1-6C)alkoxy,(1-3C)alkylsulfonamido(1-6C)alkoxy, (1-3C)alkylamido(1-6C)alkoxy,di(1-3C alkyl)amino-carboxy, hetCyc²C(═O)O—, hydroxydifluoro(1-6C)alkyl,(1-4C alkylcarboxy)(1-6C)alkyl, (1-6C)alkoxycarbonyl, hydroxylcarbonyl,aminocarbonyl, (1-3C alkoxy)aminocarbonyl, hetCyc³, halogen, CN,trifluoromethylsulfonyl, N-(1-3C alkyl)oxadiazolonyl, or hetAr⁵;

hetCyc² is a 4-6 membered heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O and optionally substituted with 1-2groups independently selected from (1-6C)alkyl, (1-4Calkylcarboxy)(1-6C)alkyl, and (1-6C)acyl;

hetCyc³ is a 4-7 membered heterocycle having 1-2 ring heteroatomsindependently selected from N and O and optionally substituted with oneor more substituents independently selected from F, CN, (1-6C)alkyl,trifluoro(1-6C)alkyl, hydroxy(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl,(1-6C)acyl-, (1-6C)alkylsulfonyl, trifluoromethylsulfonyl and (1-4Calkoxy)carbonyl;

hetAr³ is a 5-membered heteroaryl ring having 1-3 ring atomsindependently selected from N, O and S and optionally substituted with(1-6C)alkyl;

Ar³ is phenyl optionally substituted with (1-4C)alkoxy;

hetAr⁴ is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, S and O and optionally substituted withone or more substituents independently selected from (1-6C)alkyl,halogen, CN, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl,difluoro(1-6C)alkyl, fluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH₂— (3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6Calkyl)amino, (1-3C trifluoroalkoxy), fluoro(1-6C alkyl)amino,difluoro(1-6C alkyl)amino, trifluoro(1-6C alkyl)amino, and (3-4Ccycloalkyl)amino;

hetAr⁵ is a group selected from the structures:

where R^(z) is (3-4C)cycloalkyl or (1-3C)alkyl (optionally substitutedwith 1-3 fluoros), wherein each of said hetAr⁵ groups is optionallyfurther substituted with one or more groups independently selected fromF and (1-3C)alkyl optionally substituted with 1-3 fluoros;

Ar⁴ is phenyl optionally substituted with one or more groupsindependently selected from (1-6C)alkyl, halogen, CN, CF₃, CF₃O—,(1-6C)alkoxy, (1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio,hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3Calkyl)OC(═O)—;

R⁵ is (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl,halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3C alkoxy)(1-4C)alkyl,(1-4C alkyl)OC(═O)—, (1-6C)alkylthio, (3-4C)cycloalkyl, amino,aminocarbonyl, trifluoro(1-3C alkyl)amido, or phenyl (optionallysubstituted with one or more groups independently selected from halogen,(1-6C)alkyl and (1-6C)alkoxy); or

R⁴ and R⁵ together with the atoms to which they are attached form a 5-6membered saturated, partially unsaturated or unsaturated carbocyclicring optionally substituted with one or more substituents independentlyselected from (1-6C)alkyl, or

R⁴ and R⁵ together with the atoms to which they are attached form 5-6membered saturated, partially unsaturated or unsaturated heterocyclicring having a ring heteroatom selected from N, O or S, wherein saidheterocyclic ring is optionally substituted with one or two substituentsindependently selected from (1-6C alkyl)C(═O)O—, (1-6C)acyl, (1-6C)alkyland oxo, and said sulfur ring atom is optionally oxidized to S(═O) orSO₂;

R^(3a) is hydrogen, halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl,(3-6C)cycloalkyl, phenyl optionally substituted with one or moresubstituents independently selected from halogen and (1-6C)alkyl, or a5-6 membered heteroaryl ring having 1-3 ring heteroatoms independentlyselected from N, O and S and optionally substituted with one or moregroups independently selected from (1-6C)alkyl and halogen;

R^(4a) is hydrogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, phenyl[optionally substituted with one or more groups independently selectedfrom (1-6C)alkyl, halogen, CN, CF₃, CF₃O—, (1-6C)alkoxy,(1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl,(1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3C alkyl)OC(═O)—], or a5-6 membered heteroaryl ring having 1-3 ring heteroatoms independentlyselected from N, S and O and optionally substituted with 1-2substituents independently selected from (1-6C)alkyl,hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH₂— (3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6Calkyl)amino and (1-3C trifluoroalkoxy)(1-3C)trifluoroalkyl; and

R^(5a) is hydrogen, halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl,(3-6C)cycloalkyl, phenyl optionally substituted with one or moresubstituents independently selected from halogen and (1-6C)alkyl, or a5-6 membered heteroaryl ring having 1-3 ring heteroatoms independentlyselected from N, O and S and optionally substituted with one or moregroups independently selected from (1-6C)alkyl and halogen.

In one embodiment compounds of Formula I include Formula 1-2:

or stereoisomers, tautomers, or pharmaceutically acceptable salts,solvates or prodrugs thereof, wherein:

X is O, S, NH or N—CN;

Ring A is formula A-1 or A-2

Y is H, halogen, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkyl [optionallysubstituted with 1-5 fluoros], cyano(1-6C)alkyl, hydroxy(1-6C)alkyl,dihydroxy(2-6C)alkyl, aminocarbonyl(1-6C)alkyl, (1-6C)alkoxy [optionallysubstituted with 1-5 fluoros], CN, aminocarbonyl or (1-4Calkoxy)carbonyl;

R^(a), R^(b) and R^(c) are independently selected from H, halogen,(1-3C)alkyl, (1-3C)alkoxy and CN;

B is NR¹, O, a bond, CR^(d)R^(e), S or SO₂;

D is NR¹, O, a bond, CR^(f)R^(g), S or SO₂;

E is NR¹, O, a bond, or CR^(h)R^(i), S or SO₂;

F is CR^(j)R^(k);

provided that the ring formed by B, D, E, and F together with the atomsto which they are attached contains at least five atoms and zero or oneof B, D or E is NR¹ or O;

G is CR^(m)R^(n);

K is NR^(l);

R¹ is (1-6C)alkyl [optionally substituted with one to five fluoros],(1-6C)cycloalkyl [optionally substituted with one to five fluoros],(1-3C alkoxy)(2-6C)alkyl [optionally substituted with one to fivefluoros], (1-6C)alkylC(═O)— or (1-6C alkoxy)C═O—;

R^(d), R^(e), R^(f), R^(g), R^(h), R^(i), R^(j) and R^(k) areindependently H, OH, (1-6C)alkyl [optionally substituted with one tofive fluoros], (3-6C)cycloalkyl [optionally substituted with one to fivefluoros], (1-3C alkoxy)(2-6C)alkyl [optionally substituted with one tofive fluoros], hydroxy(2-6C)alkyl [optionally substituted with one tofive fluoros], (2-6C)cyanoalkyl, (1-6C)alkoxy [optionally substitutedwith one to five fluoros], or (1-3C alkoxy)(2-6C)alkoxy [optionallysubstituted with one to five fluoros],

or one of a pair of R^(d) and R^(e), or R^(f) and R^(g), or R^(h) andR^(i), or R^(j) and R^(k), together with the carbon atom to which theyare attached form a (3-6C)cycloalkyl, oxetanyl or azetidinyl ring,

or one of a pair of R^(d) and R^(e), or R^(f) and R^(g), or R^(h) andR^(i), or R^(j) and R^(k) form an oxo group,

and wherein only one of R^(d) and R^(e) can be OH and neither is OH if Bis connected to a heteroatom, and only one of R^(f) and R^(g) can be OHand neither is OH if D is connected to a heteroatom, and only one ofR^(h) and R^(i) can be OH and neither is OH if E is connected to aheteroatom, and only one of R^(j) and R^(k) can be OH and neither is OHif F is connected to a heteroatom;

R^(m) is H, (1-3C)alkyl [optionally substituted with 1-5 fluoros],cyclopropyl or cyclobutyl, and

R^(n) is H or (1-3C)alkyl [optionally substituted with 1-5 fluoros], or

R^(m) and R^(n) together form an oxo group;

R^(p) is H, (1-6C)alkyl [optionally substituted with one to fivefluoros], (3-6C)cycloalkyl [optionally substituted with one to fivefluoros], (1-3C alkoxy)(2-6C)alkyl [optionally substituted with one tofive fluoros], hydroxy(2-6C)alkyl [optionally substituted with one tofive fluoros], or (2-6C)cyanoalkyl;

Ring C is formula C-1 or C-2

R³ is (1-6C)alkyl, hydroxy(1-6C)alkyl, Ar², hetCyc¹, (3-7C)cycloalkyl,or hetAr²;

Ar² is phenyl optionally substituted with one or more groupsindependently selected from halogen and (1-6C)alkyl;

hetCyc¹ is a 5-6-membered saturated or partially unsaturatedheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and 0;

hetAr² is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, O and S and optionally substituted withone or more groups independently selected from (1-6C)alkyl and halogen;

R⁴ is OH, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluro(2-6C)alkyl, pentafluro(2-6C)alkyl,cyano(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3Calkoxy)(1-6C)alkyl, amino(1-6C)alkyl, aminocarbonyl(1-6C)alkyl,(1-3C)alkylsulfonamido(1-6C)alkyl, sulfamido(1-6C)alkyl,hydroxycarbonyl(1-6C)alkyl, hetAr³(1-6C)alkyl, Ar³(1-6C)alkyl,(1-6C)alkoxy, monofluoro(1-6C)alkoxy, difluoro(1-6C)alkoxy,trifluoro(1-6C)alkoxy, tetrafluoro(2-6C)alkoxy, pentafluoro(2-6C)alkoxy,cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy,amino(2-6C)alkoxy, hydroxyl-carbonyl(1-6C)alkoxy, hetCyc²(1-6C)alkoxy,hetAr³(1-6C)alkoxy, Ar³(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (1-3Calkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl [optionally substitutedwith F, OH, (1-6C alkyl), (1-6C) alkoxy, or (1-3C alkoxy)(1-6C)alkyl],hetAr⁴, hetAr⁴—O—, Ar⁴, hetCyc²(O)CH₂—, (1-4Calkoxycarbonyl)(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy,aminocarbonyl(1-6C)alkoxy, hetCyc²C(═O)(1-6C)alkoxy, hydroxy(1-3Calkoxy)(1-6C)alkoxy, hydroxytrifluoro(1-6C)alkoxy,(1-3C)alkylsulfonamido(1-6C)alkoxy, (1-3C)alkylamido(1-6C)alkoxy,di(1-3C alkyl)amino-carboxy, hetCyc²C(═O)O—, hydroxydifluoro(1-6C)alkyl,(1-4C alkylcarboxy)(1-6C)alkyl, (1-6C)alkoxycarbonyl, hydroxylcarbonyl,aminocarbonyl, (1-3C alkoxy)aminocarbonyl, hetCyc³, halogen, CN,trifluoromethylsulfonyl, N-(1-3C alkyl)oxadiazolonyl, hetAr⁵ orhetCyc⁴-O—;

hetCyc² is a 4-6 membered heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O and optionally substituted with 1-2groups independently selected from (1-6C)alkyl, (1-4Calkylcarboxy)(1-6C)alkyl, and (1-6C)acyl;

hetCyc³ is a 4-7 membered heterocycle having 1-2 ring heteroatomsindependently selected from N and O and optionally substituted with oneor more substituents independently selected from F, CN, (1-6C)alkyl,trifluoro(1-6C)alkyl, hydroxy(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl,(1-6C)acyl-, (1-6C)alkylsulfonyl, trifluoromethylsulfonyl and (1-4Calkoxy)carbonyl;

hetAr³ is a 5-membered heteroaryl ring having 1-3 ring atomsindependently selected from N, O and S and optionally substituted with(1-6C)alkyl;

Ar³ is phenyl optionally substituted with (1-4C)alkoxy;

hetAr⁴ is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, S and O and optionally substituted withone or more substituents independently selected from (1-6C)alkyl,halogen, CN, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl,difluoro(1-6C)alkyl, fluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH₂— (3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6Calkyl)amino, (1-3C trifluoroalkoxy), fluoro(1-6C alkyl)amino,difluoro(1-6C alkyl)amino, trifluoro(1-6C alkyl)amino, and (3-4Ccycloalkyl)amino;

hetAr⁵ is a group selected from the structures:

where R^(z) is (3-4C)cycloalkyl or (1-3C)alkyl (optionally substitutedwith 1-3 fluoros), wherein each of said hetAr⁵ groups is optionallyfurther substituted with one or more groups independently selected fromF and (1-3C)alkyl optionally substituted with 1-3 fluoros;

hetCyc⁴ is a 7-8 membered bridged heterocycle having a ring nitrogenatom and optionally substituted with one or more groups independentlyselected from (1-6C)alkyl and halogen;

Ar⁴ is phenyl optionally substituted with one or more groupsindependently selected from (1-6C)alkyl, halogen, CN, CF₃, CF₃O—,(1-6C)alkoxy, (1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio,hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3Calkyl)OC(═O)—;

R⁵ is (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl,halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3C alkoxy)(1-4C)alkyl,(1-4C alkyl)OC(═O)—, (1-6C)alkylthio, (3-4C)cycloalkyl, amino,aminocarbonyl, trifluoro(1-3C alkyl)amido, or phenyl (optionallysubstituted with one or more groups independently selected from halogen,(1-6C)alkyl and (1-6C)alkoxy); or

R⁴ and R⁵ together with the atoms to which they are attached form a 5-6membered saturated, partially unsaturated or unsaturated carbocyclicring optionally substituted with one or more substituents independentlyselected from (1-6C)alkyl, or

R⁴ and R⁵ together with the atoms to which they are attached form 5-6membered saturated, partially unsaturated or unsaturated heterocyclicring having a ring heteroatom selected from N, O or S, wherein saidheterocyclic ring is optionally substituted with one or two substituentsindependently selected from (1-6C alkyl)C(═O)O—, (1-6C)acyl, (1-6C)alkyland oxo, and said sulfur ring atom is optionally oxidized to S(═O) orSO₂;

R^(3a) is halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl,phenyl optionally substituted with one or more substituentsindependently selected from halogen and (1-6C)alkyl, or a 5-6 memberedheteroaryl ring having 1-3 ring heteroatoms independently selected fromN, O and S and optionally substituted with one or more groupsindependently selected from (1-6C)alkyl and halogen;

R^(4a) is hydrogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, phenyl[optionally substituted with one or more groups independently selectedfrom (1-6C)alkyl, halogen, CN, CF₃, CF₃O—, (1-6C)alkoxy,(1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl,(1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3C alkyl)OC(═O)—], or a5-6 membered heteroaryl ring having 1-3 ring heteroatoms independentlyselected from N, S and O and optionally substituted with 1-2substituents independently selected from (1-6C)alkyl,hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH₂— (3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6Calkyl)amino and (1-3C trifluoroalkoxy)(1-3C)trifluoroalkyl; and

R^(5a) is halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl,phenyl optionally substituted with one or more substituentsindependently selected from halogen and (1-6C)alkyl, or a 5-6 memberedheteroaryl ring having 1-3 ring heteroatoms independently selected fromN, O and S and optionally substituted with one or more groupsindependently selected from (1-6C)alkyl and halogen.

It is to be understood that in instances where two or more radicals areused in succession to define a substituent attached to a structure, thefirst named radical is considered to be terminal and the last namedradical is considered to be attached to the structure in question. Thus,for example, the radical “alkoxyalkyl” is attached to the structure inquestion by the alkyl group.

The terms “(1-6C)alkyl”, “(1-4C)alkyl” and “(1-3C)alkyl” as used hereinrefer to saturated linear monovalent hydrocarbon radicals of one to sixcarbon atoms, one to four carbon atoms, and one to three carbon atoms,respectively, or a branched saturated monovalent hydrocarbon radical ofthree to six carbon atoms, three to four carbon atoms, or three carbonatoms, respectively. Examples include, but are not limited to, methyl,ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl,2-methyl-2-propyl, 2,2-dimethylpropyl, 1-pentyl, 2-pentyl, 3-pentyl,2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl,1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl,2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.

“(1-4C)Alkoxy”, “(1-3C)alkoxy”, “(1-6C)alkoxy” and “(2-6C)alkoxy” referto an —OR radical where R is (1-4C)alkyl, (1-3C)alkyl, (1-6C)alkyl, or(2-6C)alkyl, respectively, as defined above. Examples include methoxy,ethoxy, and the like.

“(1-6)Acyl” means a RC(═O)— radical where R is a linear saturatedmonovalent hydrocarbon radical of one to five carbon atoms or a branchedsaturated monovalent hydrocarbon radical of three to five carbon atoms,e.g., methylcarbonyl, and the like.

“(1-3C Alkoxy)(1-6C)alkyl” and “(1-3C alkoxy)(1-4C)alkyl” mean a linearsaturated monovalent hydrocarbon radical of one to six carbon atoms orone to four carbon atoms, or a branched saturated monovalent hydrocarbonradical of three to six carbon atoms or three to four carbon atoms,respectively, wherein one of the carbon atoms is substituted with one(1-3C)alkoxy group as defined herein.

“(1-3C Alkoxy)(1-6C)alkoxy” means a (1-6C)alkoxy group as definedherein, wherein one of the carbon atoms is substituted with a(1-3C)alkoxy group as defined herein. Examples include methoxymethoxy,methoxyethoxy, and the like.

“(1-3C Alkoxy)aminocarbonyl” means a (1-3C alkyl)-O—NH—C(═O)— group.

“(1-6C)Alkoxycarbonyl” and “(1-4C)alkoxycarbonyl” mean a (1-6C)—O—C(═O)—and (1-4C)—O—C(═O)— group, respectively.

“(1-4C Alkoxycarbonyl)(1-6C alkoxy)” means a (1-6C) alkoxy group asdefined herein wherein one of the carbon atoms is substituted with one(1-4C alkoxy)carbonyl group, i.e., an alkyl-O—C(═O)— group.

“(1-3C Alkoxy)hydroxycarbonylalkyl” means a hydroxycarbonylalkyl groupas defined herein wherein one of the carbon atoms is substituted withone (1-3C alkoxy) group.

“Amino” means a —NRR′ group where R and R′ are independently selectedfrom hydrogen or (1-3C)alkyl as defined herein. Examples include H₂N—,CH₃NH—, (CH₃)₂N, and the like. “Amino(1-6C)alkyl” means a linearsaturated monovalent hydrocarbon radical of one to six carbon atoms or abranched saturated monovalent hydrocarbon radical of three to six carbonatoms, wherein one of the carbon atoms is substituted with one —NRR′group where R and R′ are independently selected from hydrogen or(1-3C)alkyl as defined herein. Examples include aminomethyl,methylaminoethyl, 2-ethylamino-2-methylethyl, and the like.

“Amino(2-6C)alkoxy” means a (2-6C)alkoxy group as defined herein,wherein one of the carbon atoms is substituted with one —NRR′ groupwhere R and R′ are independently selected from hydrogen or (1-3C)alkylas defined herein.

“Aminocarbonyl” means a RR′NCO— radical where R and R′ are independentlyhydrogen or (1-6C)alkyl as defined herein. Examples include H₂NCO—,dimethylaminocarbonyl, and the like.

“Aminocarbonyl(1-6C)alkyl” means a linear saturated hydrocarbon radicalof one to six carbon atoms or a branched saturated monovalenthydrocarbon radical of three to six carbons wherein one of the carbonatoms is substituted with one aminocarbonyl group as defined herein,e.g., 2-aminocarbonylethyl, 1-, 2-, or 3-dimethylaminocarbonylpropyl,and the like.

“Aminocarbonyl(1-6C)alkoxy” means a (1-6C)alkoxy as defined herein,wherein one of the carbon atoms is substituted with one aminocarbonylgroup as defined herein.

“(1-3C)Alkylamido(1-6C)alkoxy” means a (1-6C)alkoxy as defined herein,wherein one of the carbon atoms is substituted with one alkylamidogroup, i.e., substituted with a (1-3C)C(═O)NH— group.

“(1-4C alkyl)carboxy” means a R′—C(═O)O— group where R′ is (1-4C)alkyl.

“(1-4C alkylsiloxy)(1-6C)alkoxy” means a (1-6C)alkoxy group as definedherein wherein one of the carbon atoms is substituted with one (1-4Calkyl)siloxy group, e.g., a (1-4C alkyl)Si—O— group such as atert-butylsiloxy group.

“(1-3C)Alkylsulfonamido” means a (1-3C)alkylSO₂NH— radical where(1-3C)alkyl is as defined herein.

“(1-3C Alkylsulfonamido)(1-6C)alkyl” means a linear saturatedhydrocarbon radical of one to six carbon atoms or a branched saturatedmonovalent hydrocarbon radical of three to six carbons substituted withone (1-3C)alkylsulfonamido group as defined herein.

“(1-3C)Alkylsulfonamido(1-6C)alkoxy” means a (1-6C)alkoxy group asdefined herein wherein one of the carbon atoms is substituted with one(1-3C)alkylsulfonamido group as defined herein.

“Hydroxycarbonyl” means HOC(═O)—.

“(1-4C alkyl)carboxy(1-6C)alkyl” means a (1-6C)alkyl group as definedherein wherein one of the carbon atoms is substituted with a (1-4Calkyl)carboxy group as defined herein.

“Cyano(1-6C)alkyl” means a linear saturated hydrocarbon radical of oneto six carbon atoms or a branched saturated monovalent hydrocarbonradical of three to six carbons substituted with a cyano (CN) group.

“(3-6C)Cycloalkyl” means a cyclic saturated monovalent hydrocarbonradical of three to six carbon atoms, e.g., cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

“Dihydroxy(2-6C)alkyl” means a linear saturated hydrocarbon radical oftwo to six carbon atoms or a branched saturated monovalent hydrocarbonradical of three to six carbons substituted with two hydroxy (OH)groups, provided that two hydroxy groups are not both on the same carbonatom.

“Dihydroxy(2-6C)alkoxy” means a (2-6C)alkoxy group as defined herein,wherein two of the carbon atoms are substituted with a hydroxy group.

“Halogen” as used herein means F, Cl, Br or I.

“Heterocycle” refers to a saturated or partially unsaturated ring systemhaving one or more ring heteroatoms as recited for the specificheterocyclic group, wherein the heterocycle is optionally substitutedwith substituents as defined for that particular heterocyclic group.

“Heteroaryl” refers to a 5-6 membered unsaturated ringsystem having oneor more ring heteroatoms as recited for the specific heteroaryl group,wherein the heteroaryl is optionally substituted with substituents asdefined for that particular heteroaryl group.

“hetCyc²C(═O)(1-6C)alkoxy” means a (1-6C)alkoxy as defined herein,wherein one of the carbon atoms is substituted with a hetCyc²C(═O)group, wherein hetCyc² is as defined herein.

“Hydroxy(1-6C)alkyl” and “hydroxy(1-4C)alkyl” means a linear saturatedhydrocarbon radical of one to six carbon atoms or one to four carbonatoms, respectively, or a branched saturated monovalent hydrocarbonradical of three to six carbon atoms or three to four carbon atoms,respectively, wherein one of the carbon atoms is substituted with ahydroxy (OH) group.

“Hydroxy(1-6C)alkoxy” means a (1-6C)alkoxy group as defined herein,wherein one of the carbon atoms is substituted with a hydroxy group.

“Hydroxy(1-3C alkoxy)(1-6C)alkoxy” means a (1-3C alkoxy)(1-6C)alkoxy asdefined herein, wherein one of the carbon atoms is substituted with ahydroxy group.

“Hydroxydifluoro(1-6C)alkyl” means a difluoro(1-6C)alkyl group asdefined herein, wherein one of the carbon atoms is substituted with ahydroxy group.

“Hydroxytrifluoro(1-6C)alkoxy” means a trifluoro(1-6C)alkoxy group asdefined herein, wherein one of the carbon atoms is substituted with ahydroxy group.

“Hydroxycarbonylalkyl” means a linear saturated hydrocarbon radical ofone to six carbon atoms or a branched saturated monovalent hydrocarbonradical of three to six carbons substituted with one —COOH group.Examples include 2-hydroxycarbonylethyl, 1-, 2-, or3-hydroxycarbonylpropyl, and the like.

“Isoindoline-1,3-dionyl(1-6C)alkoxy” means a (1-6C)alkoxy group asdefined herein, wherein one of the carbon atoms is substituted with anisoindoline-1,3-dionyl group.

“Monofluoro(1-6C)alkyl”, “difluoro(1-6C)alkyl” and“trifluoro(1-6C)alkyl” refer to a (1-6C)alkyl group as defined hereinwherein one to three hydrogen atoms, respectively, is replaced by afluoro group.

“Tetrafluoro(2-6C)alkyl” and “pentafluoro(2-6C)alkyl” refer to a linearsaturated monovalent hydrocarbon radical of two to six carbon atoms or abranched saturated monovalent hydrocarbon radical of three to six carbonatoms wherein four to five hydrogen atoms, respectively, is replaced bya fluoro group.

“Trifluro(1-3C alkyl)amido” means a (1-3C alkyl)C(═O)NH— group whereinone of the carbons is substituted with three fluoros.

“Trifluoro(1-6C)alkoxy” means a (1-6C)alkoxy group as defined herein,wherein one of the carbon atoms is substituted with three fluoros.

“Sulfamido(1-6C)alkyl” means a linear saturated hydrocarbon radical ofone to six carbon atoms or a branched saturated monovalent hydrocarbonradical of three to six carbons substituted with one sulfamido(H₂NSO₂NH—) group.

It should be noted that compounds of the invention may contain groupsthat may exist in tautomeric forms, such as heteroatom substitutedheteroaryl or heterocyclic groups and the like, which are illustrated inthe following general and specific examples:

where G′=O, S, or NR, and though one form is named, described, displayedand/or claimed herein, all the tautomeric forms are intended to beinherently included in such name, description, display and/or claim.

In one embodiment of Formula I, X is O.

In one embodiment of Formula I, X is S.

In one embodiment of Formula I, X is NH.

In one embodiment of Formula I, X is N—CN.

In one embodiment of Formula I, Y is H.

In one embodiment of Formula I, Y is halogen. In one embodiment, Y is F,Cl or Br.

In one embodiment of Formula I, Y is (1-3C alkoxy)(1-6C)alkyl. In oneembodiment, Y is CH₃OCH₂—.

In one embodiment of Formula I, Y is (1-6C)alkyl optionally substitutedwith 1-5 fluoros. In one embodiment, Y is methyl, ethyl, propyl,isopropyl or trifluoromethyl.

In one embodiment of Formula I, Y is cyano(1-6C)alkyl. In oneembodiment, Y is CNCH₂—.

In one embodiment of Formula I, Y is hydroxy(1-6C)alkyl. In oneembodiment, Y is HOCH₂.

In one embodiment of Formula I, Y is dihydroxy(2-6C)alkyl. In oneembodiment, Y is HOCH₂CH(OH).

In one embodiment of Formula I, Y is aminocarbonyl(1-6C)alkyl. In oneembodiment, Y is H₂NC(═O)CH₂CH₂—, CH₃NHC(═O)CH₂CH₂—, or(CH₃)₂NC(═O)CH₂CH₂—.

In one embodiment of Formula I, Y is (1-6C)alkoxy optionally substitutedwith 1-5 fluoros. In one embodiment, Y is CH₃O—, CH₃CH₂O—, CF₃O— orCF₃CH₃O—.

In one embodiment of Formula I, Y is CN.

In one embodiment of Formula I, Y is aminocarbonyl. In one embodiment, Yis H₂NC(═O)—.

In one embodiment of Formula I, Y is (1-4C alkoxy)carbonyl. In oneembodiment, Y is CH₃OC(═O)—.

In one embodiment of Formula I, Y is H, halogen or (1-3Calkoxy)(1-6C)alkyl.

In one embodiment of Formula I, R^(a), R^(b) and R^(c) are hydrogen.

In one embodiment of Formula I, R^(a), R^(b) and R^(c) are independentlyselected from halogen, (1-3C)alkyl, (1-3C)alkoxy and CN.

In one embodiment of Formula I, one of R^(a), R^(b) and R^(c) isselected from halogen, (1-3C)alkyl, (1-3C)alkoxy and CN and the othertwo are hydrogen.

In one embodiment of Formula I, one of R^(a), R^(b) and R^(c) isselected from halogen and (1-3C)alkoxy and the other two are hydrogen.

In one embodiment of Formula I, zero to four of R^(d), R^(e), R^(f),R^(g), R^(h), R^(i), R^(j) and R^(k) are independently H, OH,(1-6C)alkyl [optionally substituted with one to five fluoros],(3-6C)cycloalkyl [optionally substituted with one to five fluoros],(1-3C alkoxy)(2-6C)alkyl [optionally substituted with one to fivefluoros], hydroxy(2-6C)alkyl [optionally substituted with one to fivefluoros], (2-6C)cyanoalkyl, (1-6C)alkoxy [optionally substituted withone to five fluoros], or (1-3C alkoxy)(2-6C)alkoxy [optionallysubstituted with one to five fluoros], or one of a pair of R^(d) andR^(e), or R^(f) and R^(g), or R^(h) and R^(i), or R^(j) and R^(k),together with the carbon atom to which they are attached form a(3-6C)cycloalkyl, oxetanyl or azetidinyl ring, or one of a pair of R^(d)and R^(e), or R^(f) and R^(g), or R^(h) and R^(i), or R^(j) and R^(k)form an oxo group, and the remainder are hydrogen, wherein only one ofR^(d) and R^(e) can be OH and neither is OH if B is connected to aheteroatom, and only one of R^(f) and R^(g) can be OH and neither is OHif D is connected to a heteroatom, and only one of R^(h) and R^(i) canbe OH and neither is OH if E is connected to a heteroatom, and only oneof R^(j) and R^(k) can be OH and neither is OH if F is connected to aheteroatom.

In one embodiment of Formula I, zero to four of R^(d), R^(e), R^(f),R^(g), R^(h), R^(i), R^(j) and R^(k) are independently OH, (1-6C)alkyl[optionally substituted with one to five fluoros], (3-6C)cycloalkyl[optionally substituted with one to five fluoros], (1-3Calkoxy)(2-6C)alkyl [optionally substituted with one to five fluoros],(1-6C)alkoxy [optionally substituted with one to five fluoros], or (1-3Calkoxy)(2-6C)alkoxy [optionally substituted with one to five fluoros],or one of a pair of R^(d) and R^(e), or R^(f) and R^(g), or R^(h) andR^(i), or R^(j) and R^(k), together with the carbon atom to which theyare attached form a (3-6C)cycloalkyl, oxetanyl or azetidinyl ring, orone of a pair of R^(d) and R^(e), or R^(f) and R^(g), or R^(h) andR^(i), or R^(j) and R^(k) form an oxo group, and the remainder arehydrogen, wherein only one of R^(d) and R^(e) can be OH and neither isOH if B is connected to a heteroatom, and only one of R^(f) and R^(g)can be OH and neither is OH if D is connected to a heteroatom, and onlyone of R^(h) and R^(i) can be OH and neither is OH if E is connected toa heteroatom, and only one of R^(j) and R^(k) can be OH and neither isOH if F is connected to a heteroatom.

In one embodiment of Formula I, zero to four of R^(d), R^(e), R^(f),R^(g), R^(h), R^(i), R^(j) and R^(k) are independently OH, methyl,methoxy, cyclopropyl, or 2-methoxyethoxy, or one of a pair of R^(d) andR^(e), or R^(f) and R^(g), or R^(h) and R^(i), or R^(j) and R^(k),together with the carbon atom to which they are attached form a(3-6C)cycloalkyl, oxetanyl or azetidinyl ring, or one of a pair of R^(d)and R^(e), or R^(f) and R^(g), or R^(h) and R^(i), or R^(j) and R^(k)form an oxo group, and the remainder are hydrogen, wherein only one ofR^(d) and R^(e) can be OH and neither is OH if B is connected to aheteroatom, and only one of R^(f) and R^(g) can be OH and neither is OHif D is connected to a heteroatom, and only one of R^(h) and R^(i) canbe OH and neither is OH if E is connected to a heteroatom, and only oneof R^(j) and R^(k) can be OH and neither is OH if F is connected to aheteroatom.

In one embodiment of Formula I, zero to two of R^(d), R^(e), R^(f),R^(g), R^(h), R^(i), R^(j) and R^(k) are independently OH, (1-6C)alkyl[optionally substituted with one to five fluoros], (3-6C)cycloalkyl[optionally substituted with one to five fluoros], (1-3Calkoxy)(2-6C)alkyl [optionally substituted with one to five fluoros],hydroxy(2-6C)alkyl [optionally substituted with one to five fluoros],(2-6C)cyanoalkyl, (1-6C)alkoxy [optionally substituted with one to fivefluoros], or (1-3C alkoxy)(2-6C)alkoxy [optionally substituted with oneto five fluoros], or one of a pair of R^(d) and R^(e), or R^(f) andR^(g), or R^(h) and R^(i), or R^(j) and R^(k), together with the carbonatom to which they are attached form a (3-6C)cycloalkyl, oxetanyl orazetidinyl ring, or one of a pair of R^(d) and R^(e), or R^(f) andR^(g), or R^(h) and R^(i), or R^(j) and R^(k) form an oxo group, and theremainder are hydrogen, wherein only one of R^(d) and R^(e) can be OHand neither is OH if B is connected to a heteroatom, and only one ofR^(f) and R^(g) can be OH and neither is OH if D is connected to aheteroatom, and only one of R^(h) and R^(i) can be OH and neither is OHif E is connected to a heteroatom, and only one of R^(j) and R^(k) canbe OH and neither is OH if F is connected to a heteroatom.

In one embodiment of Formula I, zero to two of R^(d), R^(e), R^(f),R^(g), R^(h), R^(i), R^(j) and R^(k) are independently OH, (1-6C)alkyl[optionally substituted with one to five fluoros], (3-6C)cycloalkyl[optionally substituted with one to five fluoros], (1-3Calkoxy)(2-6C)alkyl [optionally substituted with one to five fluoros],(1-6C)alkoxy [optionally substituted with one to five fluoros], or (1-3Calkoxy)(2-6C)alkoxy [optionally substituted with one to five fluoros],or one of a pair of R^(d) and R^(e), or R^(f) and R^(g), or R^(h) andR^(i), or R^(j) and R^(k), together with the carbon atom to which theyare attached form a (3-6C)cycloalkyl, oxetanyl or azetidinyl ring, orone of a pair of R^(d) and R^(e), or R^(f) and R^(g), or R^(h) andR^(i), or R^(j) and R^(k) form an oxo group, and the remainder arehydrogen, wherein only one of R^(d) and R^(e) can be OH and neither isOH if B is connected to a heteroatom, and only one of R^(f) and R^(g)can be OH and neither is OH if D is connected to a heteroatom, and onlyone of R^(h) and R^(i) can be OH and neither is OH if E is connected toa heteroatom, and only one of R^(j) and R^(k) can be OH and neither isOH if F is connected to a heteroatom.

In one embodiment of Formula I, zero to two of R^(d), R^(e), R^(f),R^(g), R^(h), R^(i), R^(j) and R^(k) are independently OH, methyl,methoxy, cyclopropyl, or 2-methoxyethoxy, or one of a pair of R^(d) andR^(e), or R^(f) and R^(g), or R^(h) and R^(i), or R^(j) and R^(k),together with the carbon atom to which they are attached form a(3-6C)cycloalkyl, oxetanyl or azetidinyl ring, or one of a pair of R^(d)and R^(e), or R^(f) and R^(g), or R^(h) and R^(i), or R^(j) and R^(k)form an oxo group, and the remainder are hydrogen, wherein only one ofR^(d) and R^(e) can be OH and neither is OH if B is connected to aheteroatom, and only one of R^(f) and R^(g) can be OH and neither is OHif D is connected to a heteroatom, and only one of R^(h) and R^(i) canbe OH and neither is OH if E is connected to a heteroatom, and only oneof R^(j) and R^(k) can be OH and neither is OH if F is connected to aheteroatom.

In one embodiment of Formula I, one of R^(d), R^(e), R^(f), R^(g),R^(h), R^(i), R^(j) and R^(k) is halogen or (1-3C)alkoxy, and theremainder are hydrogen.

In one embodiment of Formula I, R^(d), R^(e), R^(f), R^(g), R^(h),R^(i), R^(j) and R^(k) are hydrogen.

As used herein, the phrase “one of a pair of R^(d) and R^(e), or R^(f)and R^(g), or R^(h) and R^(i), or R^(j) and R^(k), together with thecarbon atom to which they are attached form a (3-6C)cycloalkyl, oxetanylor azetidinyl ring” refers a spirocyclic (3-6C)cycloalkyl, oxetanyl orazetidinyl ring formed from a pair of said R groups, wherein each Rgroup of said pair is attached to the same carbon atom. Examples of suchstructures include, but are not limited to the following:

and the like, wherein the remaining R^(d), R^(e), R^(f), R^(g), R^(h),R^(i), R^(j) and R^(k) are independently H, OH, (1-6C)alkyl [optionallysubstituted with one to five fluoros], (3-6C)cycloalkyl [optionallysubstituted with one to five fluoros], (1-3C alkoxy)(2-6C)alkyl[optionally substituted with one to five fluoros], hydroxy(2-6C)alkyl[optionally substituted with one to five fluoros], or (2-6C)cyanoalkyland R¹ is H, (1-6C)alkyl [optionally substituted with one to fivefluoros], (3-6C)cycloalkyl [optionally substituted with one to fivefluoros], (1-3C alkoxy)(2-6C)alkyl [optionally substituted with one tofive fluoros], hydroxy(2-6C)alkyl [optionally substituted with one tofive fluoros], or (2-6C)cyanoalkyl.

As used herein, the phrase “one of a pair of R^(d) and R^(e), or R^(f)and R^(g), or R^(h) and R^(i), or R^(j) and R^(k), together with thecarbon atom to which they are attached form an oxo group” refers to anoxo group formed from a pair of said R groups, wherein each R group ofsaid pair is attached to the same carbon atom. Examples of suchstructures include, but are not limited to the following:

and the like, wherein the remaining R^(d), R^(e), R^(f), R^(g), R^(h),R^(i), R^(j) and R^(k) are independently H, OH, (1-6C)alkyl [optionallysubstituted with one to five fluoros], (3-6C)cycloalkyl [optionallysubstituted with one to five fluoros], (1-3C alkoxy)(2-6C)alkyl[optionally substituted with one to five fluoros], hydroxy(2-6C)alkyl[optionally substituted with one to five fluoros], or (2-6C)cyanoalkyland R¹ is H, (1-6C)alkyl [optionally substituted with one to fivefluoros], (3-6C)cycloalkyl [optionally substituted with one to fivefluoros], (1-3C alkoxy)(2-6C)alkyl [optionally substituted with one tofive fluoros], hydroxy(2-6C)alkyl [optionally substituted with one tofive fluoros], or (2-6C)cyanoalkyl.

The phrase “R^(d), R^(e), R^(f), R^(g), R^(h), R^(i), R^(j) and R^(k)are independently H, OH, (1-6C)alkyl [optionally substituted with one tofive fluoros], (3-6C)cycloalkyl [optionally substituted with one to fivefluoros], (1-3C alkoxy)(2-6C)alkyl [optionally substituted with one tofive fluoros], hydroxy(2-6C)alkyl [optionally substituted with one tofive fluoros], or (2-6C)cyanoalkyl, or one of a pair of R^(d) and R^(e),or R^(f) and R^(g), or R^(h) and R^(i), or R^(j) and R^(k), togetherwith the carbon atom to which they are attached form a (3-6C)cycloalkyl,oxetanyl or azetidinyl ring, or one of a pair of R^(d) and R^(e), orR^(f) and R^(g), or R^(h) and R^(i), or R^(j) and R^(k) form an oxogroup” refers to a compound having a spirocyclic group which is formedfrom a first pair of said R groups, wherein each R group of said firstpair is attached to a first carbon atom, and further contains an oxogroup formed from a second pair of said R groups, wherein each R groupof said second pair is attached to a second carbon atom. Examples ofsuch structures include, but are not limited to the following:

and the like, wherein the remaining groups such as R^(f), R^(g), R^(h),R^(i), R^(j) and R^(k) are independently selected from H, OH,(1-6C)alkyl [optionally substituted with one to five fluoros],(3-6C)cycloalkyl [optionally substituted with one to five fluoros],(1-3C alkoxy)(2-6C)alkyl [optionally substituted with one to fivefluoros], hydroxy(2-6C)alkyl [optionally substituted with one to fivefluoros], and (2-6C)cyanoalkyl and R1 is H, (1-6C)alkyl [optionallysubstituted with one to five fluoros], (3-6C)cycloalkyl [optionallysubstituted with one to five fluoros], (1-3C alkoxy)(2-6C)alkyl[optionally substituted with one to five fluoros], hydroxy(2-6C)alkyl[optionally substituted with one to five fluoros], or (2-6C)cyanoalkyl.

In one embodiment of Formula I, Ring A is formula A-1.

In one embodiment of Formula I, Ring A is formula A-1, where B is a bondor CR^(d)R^(e), D is a bond or CR^(f)R^(g), E is a bond or CR^(h)R^(i),and F is CR^(j)R^(k), provided that the ring formed by B, D, E, and Ftogether with the atoms to which they are attached contains at leastfive atoms, where R^(d), R^(e), R^(f), R^(g), R^(h), R^(i), R^(j), andR^(k) are as defined for Formula I.

Examples of such ring systems include the structures:

where R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), R^(h), R^(i),R^(j), R^(k) and Y are as defined for Formula I. In one embodiment ofFormula I, Ring A is formula A-1, where B is a bond or CR^(d)R^(e), D isa bond or CR^(f)R^(g), E is a bond or CR^(h)R^(i), and F is CR^(j)R^(k),provided that the ring formed by B, D, E, and F together with the atomsto which they are attached contains 5-6 atoms.

In one embodiment of Formula I, Ring A when represented by formula A-1includes, but is not limited to, the following structures:

where R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), R^(h), R^(i),R^(j), R^(k) and Y are as defined for Formula I. In one embodiment ofthe above structures, R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g),R^(h), R^(i), R^(j), R^(k) and Y are as defined for Formula 1-2. In oneembodiment of the above structures, and R^(a), R^(b), R, R^(d), R^(e),R^(f), R^(g), R^(h), R^(i), R^(j), R^(k) and Y are as defined forFormula 1-2.

In one embodiment of Formula I, Ring A when represented by formula A-1is selected from the structures:

In one embodiment of Formula I, Ring A is A-1, wherein B is O, a bond orCR^(d)R^(e); D is O, a bond or CR^(f)R^(g); E is O, a bond orCR^(h)R^(i); and F is CR^(j)R^(k), provided that the ring formed by B,D, E, and F together with the atoms to which they are attached containsat least five atoms and contains one oxygen atom, where R^(d), R^(e),R^(f), R^(g), R^(h), R^(i), R^(j), and R^(k) are as defined for FormulaI. Examples of such ring systems include, but are not limited to, thefollowing structures:

where R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), R^(h), R^(i),R^(j), R^(k) and Y are as defined for Formula I. In one embodiment ofthe above structures, and R^(a), R^(b), R^(c), R^(d), R^(e), R^(f),R^(g), R^(h), R^(i), R^(j), R^(k) and Y are as defined for Formula 1-2.

In one embodiment of Formula I, Ring A when represented by formula A-1is selected from the structures:

In one embodiment of Formula I, Ring A is formula A-1, wherein B is NR¹,a bond or CR^(d)R^(e); D is NR¹, a bond or CR^(f)R^(g); E is NR¹, a bondor CR^(h)R^(i); and F is CR^(j)R^(k), provided that the ring formed byB, D, E, and F together with the atoms to which they are attachedcontains at least five atoms and contains one nitrogen atom, whereR^(d), R^(e), R^(f), R^(g), R^(h), R^(i), R^(j), and R^(k) are asdefined for Formula I.

In one embodiment of Formula I, Ring A when represented by formula A-1includes, but is not limited to, the following structures:

and the like, where R¹, R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g),R^(h), R^(i), R^(j), R^(k) and Y are as defined for Formula I. In oneembodiment of the above structures, and R^(a), R^(b), R, R^(d), R^(e),R^(f), R^(g), R^(h), R^(i), R^(j), R^(k) and Y are as defined forFormula 1-2.

In one embodiment of Formula I, Ring A when represented by formula A-1is selected from the structures:

In one embodiment of Formula I, Ring A when represented by formula A-1includes, but is not limited to, the following structures:

and the like, where R¹, R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g),R^(h), R^(i), R^(j), R^(k) and Y are as defined for Formula I. In oneembodiment of the above structures, and R^(a), R^(b), R, R^(d), R^(e),R^(f), R^(g), R^(h), R^(i), R^(j), R^(k) and Y are as defined forFormula 1-2.

In one embodiment of Formula I, Ring A when represented by formula A-1is selected from the structures:

In one embodiment of Formula I, Ring A is formula A-1, wherein B is NR¹or O; D is a bond or CR^(f)R^(g); E is a bond or CR^(h)R^(i); and F isCR^(j)R^(k), provided that the ring formed by B, D, E, and F togetherwith the atoms to which they are attached contains at least five atoms,where R^(e), R^(f), R^(g), R^(h), R^(i), R^(j), and R^(k) are as definedfor Formula I.

In one embodiment of Formula I, Ring A is formula A-1, wherein B is abond or CR^(d)R^(e); D is NR¹ or O; E is a bond or CR^(h)R^(i); and F isCR^(j)R^(k), provided that the ring formed by B, D, E, and F togetherwith the atoms to which they are attached contains at least five atoms,where R^(d), R^(e), R^(h), R^(i), R^(j), and R^(k) are as defined forFormula I.

In one embodiment of Formula I, Ring A is formula A-2, where G isCR^(m)R^(n) and K is NR¹, and R^(m), R^(n), R^(p) and R¹ are as definedfor Formula I.

In one embodiment of Formula I, Ring A is formula A-2, where G isCR^(m)R^(n) and K is NR^(l); R^(m) is H, (1-3C)alkyl [optionallysubstituted with 1-5 fluoros], cyclopropyl or cyclobutyl; R^(n) is H or(1-3C)alkyl [optionally substituted with 1-5 fluoros]; and R^(l) andR^(p) are as defined for Formula I.

In one embodiment of Formula I, Ring A is formula A-2, where G isCR^(m)R^(n) and K is NR^(l); R^(m) and R^(n) together form an oxo group;and R^(I) and R^(p) are as defined for Formula I.

In one embodiment of Formula I, Ring A when represented by formula A-2is selected from the structures:

and the like, where R^(l) and R^(p) are as defined for Formula I.

In one embodiment of Formula I, Ring A when represented by formula A-2

Reference will now be made to Ring C.

In one embodiment, Ring C is formula C-1:

where R³, R⁴ and R⁵ are as defined for Formula I.

In one embodiment, R³ is (1-6C)alkyl. In one embodiment, R³ is methyl orethyl.

In one embodiment, R³ is hydroxy(1-6C)alkyl. An example of R³ is2-hydroxyethyl.

In one embodiment, R³ is Ar², where Ar² is phenyl optionally substitutedwith one or more groups independently selected from halogen and(1-6C)alkyl.

In one embodiment, R³ when represented by Ar² is phenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl,4-methylphenyl, 3-chlorophenyl, 3-chloro-4-fluorophenyl or3-chloro-2-fluorophenyl. In one embodiment, R³ when represented by Ar²is phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2-methylphenyl, 3-methylphenyl or 4-methylphenyl. In one embodiment, R³is phenyl.

In one embodiment, R³ is hetCyc¹, where hetCyc¹ is a 5-6-memberedsaturated or partially unsaturated heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O. In one embodiment, R³is a pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, piperidinyl,piperazinyl, tetrahydropyranyl, or morpholinyl ring. In one embodiment,R³ is tetrahydro-2H-pyran-4-yl.

In one embodiment, R³ is (3-7C)cycloalkyl. In one embodiment R³ iscyclohexyl.

In one embodiment, R³ is hetAr², where hetAr² is 5-6 membered heteroarylring having 1-3 ring heteroatoms independently selected from N, O and Sand optionally substituted with one or more substituents independentlyselected from (1-6C)alkyl and halogen. In one embodiment, R³ is thienyl,furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidyl,pyrazinyl, or pyridazinyl optionally substituted with one or moresubstituents independently selected from (1-6C)alkyl and halogen. In oneembodiment, R³ is pyrazolyl, pyridyl or pyridazinyl optionallysubstituted with one or more groups independently selected from(1-6C)alkyl and halogen. In one embodiment, R³ is pyrazolyl, pyridyl orpyridazinyl optionally substituted with (1-6C)alkyl or halogen. In oneembodiment, R³ when represented by hetAr² is 1-methyl-1H-pyrazol-4-yl,pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyridazinyl or 3-chloropyrid-5-yl.

In one embodiment, R³ is selected from Ar² and hetAr².

In one embodiment, R³ is Ar². In one embodiment, R³ is phenyl.

In one embodiment, R⁴ is OH. An examples of a C-1 ring when R⁴ is OHincludes the following tautomeric structures:

In one embodiment, R⁴ is (1-6C)alkyl. In one embodiment, R⁴ is methyl,ethyl, isopropyl or tert-butyl.

In one embodiment, R⁴ is monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl or pentafluoro(2-6C)alkyl.In one embodiment, R⁴ is fluoromethyl, 2-fluoroethyl, difluoromethyl and2,2-difluoroethyl, trifluoromethyl, 2,2,2-trifluoroethyl,3,3,3-trifluoropropyl, 2,2,3,3-tetrafluoropropyl or2,2,3,3,3-pentafluoropropyl.

In one embodiment, R⁴ is trifluoro(1-6C)alkyl. In one embodiment, R⁴ isCF₃.

In one embodiment, R⁴ is cyano(1-6C)alkyl. In one embodiment, R⁴ iscyanomethyl or 2-cyanopropan-2-yl.

In one embodiment, R⁴ is hydroxy(1-6C)alkyl. In one embodiment, R⁴ ishydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropylor 1-hydroxy-2-methylpropan-2-yl.

In one embodiment, R⁴ is dihydroxy(2-6C)alkyl. In one embodiment, R⁴ is2,3-dihydroxypropyl.

In one embodiment, R⁴ is (1-3C alkoxy)(1-6C)alkyl. In one embodiment, R⁴is methoxymethyl, 2-methoxyethyl or 3-methoxypropyl.

In one embodiment, R⁴ is amino(1-6C)alkyl. In one embodiment, R⁴ isaminomethyl, 2-aminoethyl or 3-aminopropyl.

In one embodiment, R⁴ is aminocarbonyl(1-6C)alkyl. In one embodiment, R⁴is aminocarbonylmethyl and 2-(aminocarbonyl)ethyl.

In one embodiment, R⁴ is (1-3C)alkylsulfonamido(1-6C)alkyl. In oneembodiment, R⁴ is CH₃SO₂NHCH₂— or CH₃SO₂NHCH₂CH₂—.

In one embodiment, R⁴ is hydroxycarbonyl(1-6C)alkyl. In one embodiment,R⁴ is HOC(═O)CH₂— and HOC(═O)CH₂CH₂—.

In one embodiment, R⁴ is hetAr³(1-6C)alkyl, where hetAr³ is a 5-memberedheteroaryl ring having 1-3 ring atoms independently selected from N, Sand O and optionally substituted with (1-6C)alkyl. In one embodiment,hetAr³ is a thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl oroxadiazolyl ring optionally substituted with (1-6C)alkyl. In oneembodiment, R⁴ when represented by hetAr³(1-6C)alkyl is(1-methyl-1H-1,2,4-triazol-3-yl)methyl or(5-methyl-1,3,4-oxadiazol-2-yl)methyl.

In one embodiment, R⁴ is Ar³(1-6C)alkyl, where phenyl optionallysubstituted with (1-4C)alkoxy or hydroxy(1-4C)alkyl. In one embodiment,Ar³(1-6C)alkyl is benzyl.

In one embodiment, R⁴ is (1-6C)alkoxy. Examples include methoxy andethoxy.

In one embodiment, R⁴ is monofluoro(1-6C)alkoxy, difluoro(1-6C)alkoxytrifluoro(1-6C)alkoxy, tetrafluoro(2-6C)alkoxy orpentafluoro(2-6C)alkoxy. In one embodiment, R⁴ is fluoromethoxy,2-fluoroethoxy, 2,2-difluoromethoxy, trifluoromethoxy,2,2,2-trifluoroethoxy or 2,2-difluoroethoxy. In one embodiment, R⁴ is2-fluoroethoxy.

In one embodiment, R⁴ is cyano(1-6C)alkoxy. In one embodiment, R⁴ iscyanomethoxy or 2-cyanoethoxy.

In one embodiment, R⁴ is hydroxy(1-6C)alkoxy. In one embodiment, R⁴ is2-hydroxy-2-methylpropoxy, 2-hydroxyethoxy, 2-hydroxypropoxy,2-hydroxy-2-methylpropoxy or 2-hydroxybutoxy.

In one embodiment, R⁴ is dihydroxy(2-6C)alkoxy. In one embodiment, R⁴ is2,3-dihydroxypropoxy or 3-hydroxy-2-(hydroxymethyl)propoxy.

In one embodiment, R⁴ is amino(2-6C)alkoxy. In one embodiment, R⁴ isH₂NCH₂CH₂O— or (CH₃)₃NCH₂CH₂O—.

In one embodiment, R⁴ is hetCyc²(1-6C)alkoxy, where hetCyc² is a 4-6membered heterocyclic ring having 1-2 ring heteroatoms independentlyselected from N and O, wherein hetCyc² is optionally substituted with1-2 groups independently selected from (1-6C)alkyl, (1-4Calkoxy)carbonyl, and (1-6C)acyl. In one embodiment, hetCyc² isoxetaynyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or 1,3-dioxolanyloptionally substituted with 1-2 groups independently selected from(1-6C)alkyl, (1-4C alkoxy)carbonyl and (1-6C)acyl. In one embodiment, R⁴when represented by hetCyc²(1-6C)alkoxy is oxetan-2-ylmethoxy,2-(oxetan-2-yl)propoxy, (2,2-dimethyl-1,3-dioxolan-4-yl)methoxy,(1,3-dioxolan-4-yl)methoxy, 2-morpholinoethoxy, 2-morpholinomethoxy,piperazinylethyoxy, piperidinylethoxy or piperidinylmethoxy optionallysubstituted with 1-2 groups independently selected from (1-6C)alkyl,(1-4C alkoxy)carbonyl and (1-6C)acyl. In one embodiment, R⁴ isrepresented by the structures:

In one embodiment, R⁴ is hetAr³(1-6C)alkoxy, where hetAr³ is a5-membered heteroaryl ring having 1-3 ring atoms independently selectedfrom N, S and O and optionally substituted with (1-6C)alkyl. In oneembodiment, hetAr³ is a thienyl, furyl, imidazolyl, pyrazolyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolylor oxadiazolyl ring optionally substituted with (1-6C)alkyl. In oneembodiment, hetAr³ is triazolyl or oxadiazolyl ring optionallysubstituted with a (1-6C)alkyl group such as a methyl group. In oneembodiment, R⁴ when represented by hetAr³(1-6C)alkoxy is(1-methyl-1H-1,2,4-triazol-3-yl)methoxy or(5-methyl-1,3,4-oxadiazol-2-yl)methoxy, which can be represented by thestructures:

In one embodiment, R⁴ is Ar³(1-6C)alkoxy, where Ar³ is phenyl optionallysubstituted with (1-4C)alkoxy. In one embodiment, R⁴ is phenylmethoxy or(4-methoxyphenyl)methoxy having the structures:

In one embodiment, R⁴ is (1-4C alkoxy)(1-6C)alkoxy. In one embodiment,R⁴ is (2-methoxy)ethoxy having the structure:

In one embodiment, R⁴ is (1-3Calkylsulfonyl)(1-6C)alkoxy. In oneembodiment, R⁴ is (2-methylsulfonyl)ethoxy having the structure:

In one embodiment, R⁴ is (3-6C)cycloalkyl optionally substituted with F,OH, (1-6C alkyl), (1-6C)alkoxy or (1-3C alkoxy)(1-6C)alkyl. Examplesinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,2-hydroxycyclobutyl. In one embodiment, R⁴ is cyclopropyl or2-hydroxycyclobutyl. In one embodiment, R⁴ is cyclopropyl.

In one embodiment, R⁴ is hetAr⁴, where hetAr⁴ is a 5-6 memberedheteroaryl ring having 1-3 ring heteroatoms independently selected fromN, S and O and optionally substituted with one or more substituentsindependently selected from (1-6C)alkyl, halogen, CN,hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, difluoro(1-6C)alkyl,fluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH₂— (3-6Ccycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy,(1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6C alkyl)amino, (1-3Ctrifluoroalkoxy), fluoro(1-6C alkyl)amino, difluoro(1-6C alkyl)amino,trifluoro(1-6C alkyl)amino, and (3-4C cycloalkyl)amino.

In one embodiment, R⁴ is hetAr⁴ where hetAr⁴ is pyridyl, pyrimidinylpyridazinyl, pyrazolyl, imidazolyl, thienyl, 1,2,4-triazolyl,1,2,3-triazolyl, thiazolyl, oxazolyl, 1,3,4-oxadiazolyl, or1,2,4-oxadiazolyl optionally substituted with one or more substituentsindependently selected from (1-6C)alkyl, halogen, CN,hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, difluoro(1-6C)alkyl,fluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH₂— (3-6Ccycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy,(1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6C alkyl)amino, (1-3Ctrifluoroalkoxy), fluoro(1-6C alkyl)amino, difluoro(1-6C alkyl)amino,trifluoro(1-6C alkyl)amino, and (3-4C cycloalkyl)amino.

In one embodiment, R⁴ is hetAr⁴ where hetAr⁴ is pyridyl, pyrimidinylpyridazinyl, pyrazolyl, imidazolyl, thienyl, 1,2,4-triazolyl,1,2,3-triazolyl, thiazolyl, oxazolyl, 1,3,4-oxadiazolyl, or1,2,4-oxadiazolyl optionally substituted with one or more substituentsindependently selected from (1-6C)alkyl, hydroxy(1-6C)alkyl,trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH₂— (3-6Ccycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy,(1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6C alkyl)amino, (1-3Ctrifluoroalkoxy)(1-3C)trifluoroalkyl and cyclopropylNH—.

In one embodiment, R⁴ is hetAr⁴, where hetAr⁴ is pyridyl, pyrimidinylpyridazinyl, pyrazolyl, imidazolyl, thionyl, 1,2,4-triazolyl,1,2,3-triazolyl, thiazolyl, oxazolyl, 1,3,4-oxadiazolyl, or1,2,4-oxadiazolyl optionally substituted with 1-3 substituentsindependently selected from fluoro, methyl, ethyl, isopropyl,cyclopropylmethyl, cyclopropyl, trifluoromethyl, 2,2,2-trifluoroethyl,methoxy, ethoxy, CN, H₂N—, (CH₃)₂N—, 2-hydroxyethyl, 2-methoxyethyl,1-(2,2,2-trifluoroethoxy)-2,2,2-trifluoroethyl, cyclopropylcarbonyl,methylsulfonyl and cyclopropylNH—.

In one embodiment, R⁴ is hetAr⁴, where hetAr⁴ is pyridyl, pyrimidinyl orpyridazinyl optionally substituted with 1-3 substituents independentlyselected from fluoro, methyl, ethyl, isopropyl, cyclopropylmethyl,cyclopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, CN,H₂N—, CH₃NH—, (CH₃)₂N—, and cyclopropylNH—.

In one embodiment, R⁴ when represented by hetAr⁴ is selected from thestructures:

In one embodiment, R⁴ is hetAr⁴—O—. In one embodiment, R⁴ is thestructure:

In one embodiment, R⁴ is Ar⁴, where Ar⁴ is phenyl optionally substitutedwith one or more groups independently selected from (1-6C)alkyl,halogen, CN, CF₃, CF₃O—, (1-6C)alkoxy, (1-6Calkyl)OC(═O)—,aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—,HOC(═O)— and (1-3C alkoxy)(1-3C alkyl)OC(═O)—. In one embodiment, Ar⁴ isphenyl optionally substituted with one or more groups independentlyselected from methyl, F, Cl, CN, methoxy, CH₃OC(═O)—, aminocarbonyl,methylaminocarbonyl, dimethylaminocarbonyl, methylthio, CH₃SO₂—,HOC(═O)— and CH₃OCH₂CH₂OC(═O)—. In one embodiment, Ar⁴ is phenyloptionally substituted with one or two of said substituents. In oneembodiment, Ar⁴ is selected from the structures:

In one embodiment, R⁴ is hetCyc²(O)CH₂, where hetCyc² is a 4-6 memberedheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and O, wherein hetCyc² is optionally substituted with 1-2 groupsindependently selected from (1-6C)alkyl, (1-4C alkoxy)carbonyl, and(1-6C)acyl. Examples of hetCyc² include oxetaynyl, tetrahydrofuranyl,tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, and 1,3-dioxolanyl rings optionally substituted with 1-2groups independently selected from (1-6C)alkyl, (1-4C alkoxy)carbonyland (1-6C)acyl. In one embodiment, R⁴ when represented by hetCyc²(0)CH₂,is selected from the structures:

In one embodiment, R⁴ is (1-4C alkoxycarbonyl)(1-6C)alkoxy. In oneembodiment, R⁴ is methoxycarbonyl(1-6C)alkoxy orethylcarbonyl(1-6C)alkoxy. A particular example isethoxycarbonylmethoxy.

In one embodiment, R⁴ is hydroxycarbonyl(1-6C)alkoxy. In one embodiment,R⁴ is hydroxycarbonylmethoxy.

In one embodiment, R⁴ is aminocarbonyl(1-6C)alkoxy. In one embodiment,R⁴ is H₂NC(═O)(1-6C)alkoxy, (1-6C alkyl)NHC(═O)(1-6C)alkoxy, ordi(1-6Calkyl)NC(═O)(1-6C)alkoxy. In one embodiment, R⁴ is H₂NC(═O)CH₂O—,H₂NC(═O)CH₂CH₂O, or CH₃CH₂NC(═O)CH₂O—.

In one embodiment, R⁴ is hetCyc²C(═O)(1-6C)alkoxy, where hetCyc² is a4-6 membered heterocyclic ring having 1-2 ring heteroatoms independentlyselected from N and O and optionally substituted with 1-2 groupsindependently selected from (1-6C)alkyl, (1-4C alkoxy)carbonyl, and(1-6C)acyl. In one embodiment, hetCyc² is oxetaynyl, tetrahydrofuranyl,tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, or 1,3-dioxolanyl optionally substituted with 1-2 groupsindependently selected from (1-6C)alkyl, (1-4C alkoxy)carbonyl and(1-6C)acyl. In one embodiment, hetCyc² is morpholinyl. In oneembodiment, R⁴ when represented by hetCyc²C(═O)(1-6C)alkoxy is thestructure:

In one embodiment, R⁴ is hydroxy(1-3C alkoxy)(1-6C)alkoxy. In oneembodiment, R⁴ is 2-hydroxy-3-methoxypropoxy, having the structure:

In one embodiment, R⁴ is hydroxytrifluoro(1-6C)alkoxy. In oneembodiment, R⁴ is 3,3,3-difluoro-2-hydroxypropoxy having the structure:

In one embodiment, R⁴ is (1-3C)alkylsulfonamido(1-6C)alkoxy. In oneembodiment, R⁴ is methanesulfonamido(1-6C)alkoxy. In one embodiment, R⁴is 2-methanesulfonamidoethoxy having the structure:

In one embodiment, R⁴ is (1-3C)alkylamido(1-6C)alkoxy. In oneembodiment, R⁴ is 2-(methylamido)ethoxy having the structure:

In one embodiment, R⁴ is di(1-3C alkyl)aminocarboxy. In one embodiment,R⁴ is dimethylaminocarboxy having the structure:

In one embodiment, R⁴ is hetCyc²C(═O)O—, where hetCyc² is a 4-6 memberedheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and O and optionally substituted with 1-2 groups independentlyselected from (1-6C)alkyl, (1-4C alkoxy)carbonyl and (1-6C)acyl. In oneembodiment, hetCyc² is oxetaynyl, tetrahydrofuranyl, tetrahydropyranyl,azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or1,3-dioxolanyl optionally substituted with 1-2 groups independentlyselected from (1-6C)alkyl, (1-4C alkoxy)carbonyl and (1-6C)acyl. In oneembodiment, hetCyc² is morpholinyl. In one embodiment, R⁴ whenrepresented by hetCyc²C(═O)O— is the structure:

In one embodiment, R⁴ is hydroxydifluoro(1-6C)alkyl. In one embodiment,R⁴ is 2,2-difluro-2-hydroxyethyl.

In one embodiment, R⁴ is (1-4C alkylcarboxy)(1-6C)alkyl. In oneembodiment, R⁴ is methylcarboxy(1-6C)alkyl. In one embodiment, R⁴ is2-(methylcarboxy)ethyl.

In one embodiment, R⁴ is (1-6C)alkoxycarbonyl. In one embodiment, R⁴ ismethoxycarbonyl or ethoxycarbonyl.

In one embodiment, R⁴ is hydroxycarbonyl.

In one embodiment, R⁴ is aminocarbonyl, that is, a RR′NCO— radical whereR and R′ are independently hydrogen or (1-6C)alkyl as defined herein. Inone embodiment, R⁴ is aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl, ethylcarbonyl or isopropylaminocarbonyl.

In one embodiment, R⁴ is (1-3C alkoxy)aminocarbonyl. In one embodiment,R⁴ is methoxyaminocarbonyl.

In one embodiment, R⁴ is hetCyc³, where is a 4-7 membered heterocyclehaving 1-2 ring heteroatoms independently selected from N and O andoptionally substituted with one or more substituents independentlyselected from F, CN, CF₃, (1-6C)alkyl, hydroxy(1-6C)alkyl, (1-3Calkoxy)(1-6C)alkyl, (1-6C)acyl-, (1-6C)alkylsulfonyl,trifluoromethylsulfonyl and (1-4C alkoxy)carbonyl. In one embodiment,hetCyc³ is tetrahydropyranyl, piperidinyl, pyrrolidinyl or azetidinyloptionally substituted with one or more substituents independentlyselected from F, CN, (1-6C)alkyl, trifluoro(1-6C)alkyl,hydroxy(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, (1-6C)acyl-,(1-6C)alkylsulfonyl, trifluoromethylsulfonyl and (1-4C alkoxy)carbonyl.In one embodiment, hetCyc³ is optionally substituted with one or two ofsaid substituents. In one embodiment, hetCyc³ is tetrahydropyranyl,piperidinyl, pyrrolidinyl or azetidinyl optionally substituted with CN,Me, CH₃C(═O)—, MeSO₂—, or CF₃SO₂—. In one embodiment, R⁴ whenrepresented by hetCyc³ is selected from the structures:

In one embodiment, R⁴ is halogen. In one embodiment, R⁴ is Br.

In one embodiment, R⁴ is CN.

In one embodiment, R⁴ is trifluoromethylsulfonyl.

In one embodiment, R⁴ is hetAr⁵, where hetAr⁵ is a group selected fromthe structures:

where R^(z) is (3-4C)cycloalkyl or (1-3C)alkyl (optionally substitutedwith 1-3 fluoros), wherein each of said hetAr⁵ groups is optionallyfurther substituted with one or more groups independently selected fromF and (1-3C)alkyl optionally substituted with 1-3 fluoros.

In one embodiment, R⁴ when represented by hetAr⁵ is selected from thestructures:

In one embodiment, R⁴ is N-(1-3C alkyl)oxadiazolonyl. In one embodiment,R⁴ is represented by the structures:

In one embodiment, R⁴ is selected from H, (1-6C)alkyl,trifluoro(1-6C)alkyl, hydroxy(1-6C)alkyl, cyano(1-6C)alkyl, (1-3Calkoxy)(1-6C)alkyl, (1-6C)alkoxy, monofluoro(1-6C)alkoxy,cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy,hetCyc²(1-6C)alkoxy, Ar³(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (1-3Calkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl, hetAr⁴, hetAr⁴—O—, Ar⁴,and hetAr⁵.

In one embodiment, R⁴ is hetAr⁴, Ar⁴, or hetAr⁵.

In one embodiment, R⁴ is hetAr⁴ or hetAr⁵.

In one embodiment, R⁴ is pyrazolyl optionally substituted with one ormore groups independently selected from (1-6C)alkyl, or a hetAr⁵ grouphaving the structure:

where R^(z) is (3-4C)cycloalkyl or (1-3C)alkyl (optionally substitutedwith 1-3 fluoros), wherein said hetAr⁵ group is optionally furthersubstituted with one or more groups independently selected from F and(1-3C)alkyl optionally substituted with 1-3 fluoros.

In one embodiment, R⁵ is (1-6C)alkyl. In one embodiment, R⁵ is methyl,ethyl, propyl, isopropyl or butyl.

In one embodiment, R⁵ is monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluro(2-6C)alkyl or pentafluro(2-6C)alkyl. Inone embodiment, R⁵ is fluoromethyl, 2-fluoroethyl, difluoromethyl,2,2-difluoroethyl, 1,3-difluoroprop-2-yl, trifluoromethyl,2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 1,1,2,2-tetrafluoropropaneor 2,2,3,3,3-pentafluoropropyl.

In one embodiment, R⁵ is halogen. In one embodiment, R⁵ is F. In oneembodiment, R⁵ is Cl. In one embodiment, R⁵ is Br.

In one embodiment, R⁵ is CN.

In one embodiment, R⁵ is (1-4C)alkoxy. In one embodiment, R⁵ is methoxyor ethoxy.

In one embodiment, R⁵ is hydroxy(1-4C)alkyl. In one embodiment, R⁵ ishydroxymethyl or 3-hydroxypropyl.

In one embodiment, R⁵ is (1-4C alkyl)OC(═O)—. In one embodiment, R⁵ isCH₃CH₂OC(═O)—.

In one embodiment, R⁵ is (1-6C)alkylthio. In one embodiment, R⁵ ismethylthio (MeS—).

In one embodiment, R⁵ is phenyl optionally substituted with one or moregroups independently selected from halogen, (1-6C)alkyl and(1-6C)alkoxy. In one embodiment, R⁵ is phenyl optionally substitutedwith one or more groups independently selected from F, C1, methyl,ethyl, methoxy and ethoxy. In one embodiment, R⁵ is phenyl.

In one embodiment, R⁵ is (3-4C)cycloalkyl. In one embodiment, R⁵ iscyclopropyl. In one embodiment, R⁵ is cyclobutyl.

In one embodiment, R⁵ is amino. In one embodiment, R⁵ is NH₂.

In one embodiment, R⁵ is aminocarbonyl. In one embodiment, R⁵ isH₂NC(═O)—.

In one embodiment, R⁵ is trifluoro(1-3C alkyl)amido. In one embodiment,R⁵ is CF₃C(═O)NH—.

In one embodiment, R⁵ is halogen, CN, (1-6C)alkyl, (1-4C)alkoxy,hydroxy(1-4C)alkyl, or phenyl optionally substituted with one or moregroups independently selected from halogen, (1-6C)alkyl and(1-6C)alkoxy.

In one embodiment, R⁵ is selected from halogen, and (1-6C)alkyl.

In one embodiment, R⁵ is selected from methyl, Cl and Br.

In one embodiment of Formula I, R⁴ is selected from H, (1-6C)alkyl,trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, (1-4Calkoxy)(1-6C)alkoxy, (3-6C)cycloalkyl, hetAr⁴, Ar⁴, and hetAr⁵; and R⁵is selected from halogen, CN, (1-6C)alkyl, (1-4C)alkoxy,hydroxy(1-4C)alkyl, (1-6C)alkylthio, and phenyl optionally substitutedwith one or more groups independently selected from halogen, (1-6C)alkyland (1-6C)alkoxy.

In one embodiment of Formula I, R⁴ is selected from hetAr⁴, Ar⁴, andhetAr⁵; and R⁵ is selected from (1-6C)alkyl.

In one embodiment of Formula I, R⁴ is selected from hetAr⁴ and hetAr⁵;and R⁵ is selected from (1-6C)alkyl.

In one embodiment of Formula I, R⁴ is hetAr⁴ and R⁵ is selected from(1-6C)alkyl.

In one embodiment of Formula I, R⁴ is pyrazolyl optionally substitutedwith one or more substituents independently selected from (1-6C)alkyl;and R⁵ is selected from (1-6C)alkyl.

In one embodiment of Formula I, R⁴ is hetAr⁵; and R⁵ is selected from(1-6C)alkyl.

In one embodiment of Formula I, R⁴ is a hetAr⁵ group having thestructure:

where R^(z) is (3-4C)cycloalkyl or (1-3C)alkyl (optionally substitutedwith 1-3 fluoros), wherein said hetAr⁵ group is optionally furthersubstituted with one or more groups independently selected from F and(1-3C)alkyl optionally substituted with 1-3 fluoros; and R⁵ is selectedfrom (1-6C)alkyl.

In one embodiment, R⁴ and R⁵ together with the atoms to which they areattached form a 5-6 membered saturated, partially unsaturated orunsaturated carbocyclic ring optionally substituted with one or moresubstituents independently selected from (1-6C)alkyl; or R⁴ and R⁵together with the atoms to which they are attached form a 5-6 memberedsaturated, partially unsaturated or unsaturated heterocyclic ring havinga ring heteroatom selected from N, O or S, wherein said heterocyclicring is optionally substituted with one or two substituentsindependently selected from (1-6C alkyl)C(═O)O—, (1-6C)acyl, (1-6C)alkyland oxo, and said sulfur ring atom is optionally oxidized to S(═O) orSO₂.

In one embodiment, R⁴ and R⁵ together with the atoms to which they areattached form a 5-6 membered saturated, partially unsaturated orunsaturated carbocyclic ring optionally substituted with one or moresubstituents independently selected from (1-6C)alkyl. In one embodiment,Ring C when R⁴ and R⁵ together with the atoms to which they are attachedform a 5-6 membered saturated or unsaturated carbocyclic ring isselected from the structures:

where R³ is as defined for Formula I. In one embodiment of saidstructures, R³ is phenyl.

In one embodiment, R⁴ and R⁵ together with the atoms to which they areattached form a 5-6 membered saturated carbocyclic ring optionallysubstituted with one or more substituents independently selected from(1-6C)alkyl, or R⁴ and R⁵ together with the atoms to which they areattached form a 5-6 membered saturated heterocyclic ring having a ringheteroatom selected from N, O or S, wherein said ring nitrogen atom isoptionally substituted with (1-6C alkyl)C(═O)O— or (1-6C)acyl, and saidsulfur ring atom is optionally oxidized to S(═O) or SO₂.

In one embodiment, R⁴ and R⁵ together with the atoms to which they areattached form a 5-6 membered saturated carbocyclic ring optionallysubstituted with one or more substituents independently selected from(1-6C)alkyl. In one embodiment, Ring C when R⁴ and R⁵ together with theatoms to which they are attached form a 5-6 membered saturatedcarbocyclic ring is selected from the structures:

where R³ is as defined for Formula I. In one embodiment of saidstructures, R³ is phenyl.

In one embodiment, R⁴ and R⁵ together with the atoms to which they areattached form a 5-6 membered saturated, partially unsaturated orunsaturated heterocyclic ring having a ring heteroatom selected from N,O or S, wherein said ring N atom is optionally substituted with (1-6Calkyl)C(═O)O—, (1-6C alkyl)C(═O)—, (1-6C)alkyl or oxo, and said S ringatom is optionally oxidized to S(═O) or SO₂. In one embodiment, Ring Cwhen R⁴ and R⁵ together with the atoms to which they are attached form a5-6 membered saturated heterocyclic ring is selected from thestructures:

where R³ is as defined for Formula I. In one embodiment of saidstructures, R³ is phenyl.

In one embodiment, R⁴ and R⁵ together with the atoms to which they areattached form a 5-6 membered saturated heterocyclic ring having a ringheteroatom selected from N, O or S, wherein said ring N atom isoptionally substituted with (1-6C alkyl)C(═O)O— or (1-6C alkyl)C(═O)—,and said S ring atom is optionally oxidized to S(═O) or SO₂. In oneembodiment, Ring C when R⁴ and R⁵ together with the atoms to which theyare attached form a 5-6 membered saturated heterocyclic ring is selectedfrom the structures:

where R³ is as defined for Formula I. In one embodiment of saidstructures, R³ is phenyl.

In one embodiment, Ring C is formula C-2

where R^(3a), R^(4a) and R^(5a) are as defined for Formula I. In oneembodiment, R^(3a), R^(4a) and R^(5a) are as defined for Formula I, withthe exception that R^(3a) and R^(5a) are not hydrogen.

In one embodiment, R^(3a) is hydrogen.

In one embodiment, R^(3a) is halogen.

In one embodiment, R^(3a) is (1-6C)alkyl. In one embodiment, R^(3a) ismethyl.

In one embodiment, R^(3a) is trifluoro(1-6C)alkyl. In one embodiment,R^(3a) is CF₃.

In one embodiment, R^(3a) is (3-6C)cycloalkyl. In one embodiment, R^(3a)is cyclopropyl.

In one embodiment, R^(3a) is phenyl optionally substituted with one ormore substituents independently selected from halogen and (1-6C)alkyl.In one embodiment, R^(3a) is phenyl, fluorophenyl or methylphenyl, forexample include phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-chlorophenyl,3-chloro-4-fluorophenyl or 3-chloro-2-fluorophenyl. In one embodiment,R^(3a) is phenyl.

In one embodiment, R^(3a) is a 5-6 membered heteroaryl ring having 1-3ring heteroatoms independently selected from N, O and S and optionallysubstituted with one or more groups independently selected from(1-6C)alkyl and halogen. In one embodiment, R^(3a) is a thienyl, furyl,imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidyl, pyrazinyl, orpyridazinyl ring optionally substituted with (1-6C)alkyl or halogen. Inone embodiment, R^(3a) is pyrazolyl, pyridyl or pyridazinyl optionallysubstituted with one or more groups independently selected from(1-6C)alkyl and halogen. In one embodiment, R^(3a) is pyrazolyl, pyridylor pyridazinyl optionally substituted with (1-6C)alkyl or halogen.

In one embodiment, R^(4a) is hydrogen.

In one embodiment, R^(4a) is (1-6C)alkyl. In one embodiment, R^(4a) ismethyl, ethyl or isopropyl.

In one embodiment, R^(4a) is trifluoro(1-6C)alkyl. In one embodiment,R^(4a) is 2,2,2-trifluoroethyl.

In one embodiment, R^(4a) is phenyl optionally substituted with one ormore groups independently selected from (1-6C)alkyl, halogen, CN, CF₃,CF₃O—, (1-6C)alkoxy, (1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio,hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3Calkyl)OC(═O)—. In one embodiment, R^(4a) is phenyl optionallysubstituted with one or more groups independently selected from methyl,F, Cl, CN, methoxy, CH₃OC(═O)—, aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl, methylthio, CH₃SO₂—, HOC(═O)— orCH₃OCH₂CH₂OC(═O)—. In certain embodiments, R^(4a) is phenyl optionallysubstituted with one or two of said substituents. In one embodiment,R^(4a) is phenyl.

In one embodiment, R^(4a) is a 5-6 membered heteroaryl ring having 1-3ring heteroatoms independently selected from N, S and O and optionallysubstituted with 1-2 substituents independently selected from(1-6C)alkyl, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl,(3-6C cycloalkyl)CH₂— (3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6Calkyl)amino, and (1-3C trifluoroalkoxy)(1-3C)trifluoroalkyl. In oneembodiment, R^(4a) is pyridyl, pyrimidinyl pyridazinyl, pyrazolyl,imidazolyl, thionyl, 1,2,4-triazolyl, 1,2,3-triazolyl, thiazolyl,oxazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl orimidazo[1,2-a]pyridinyl optionally substituted with 1-2 substituentsindependently selected from (1-6C)alkyl, hydroxy(1-6C)alkyl,trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH₂— (3-6Ccycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy,(1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6C alkyl)amino, and(1-3C trifluoroalkoxy)(1-3C)trifluoroalkyl. In one embodiment, R^(4a) ispyrazinyl.

In one embodiment, R^(5a) is as defined for Formula I.

In one embodiment, R^(5a) is selected from hydrogen, halogen,(1-6C)alkyl and phenyl.

In one embodiment, R^(5a) is hydrogen.

In one embodiment, R^(5a) is halogen.

In one embodiment, R^(5a) is (1-6C)alkyl. In one embodiment, R^(5a) ismethyl.

In one embodiment, R^(5a) is phenyl.

In one embodiment, Ring C is formula C-2, in which R^(3a) is(1-6C)alkyl, trifluoro(1-6C)alkyl or phenyl; R^(4a) is (1-6C)alkyl,trifluoro(1-6C)alkyl, phenyl or pyrazinyl; and R^(5a) is hydrogen,(1-6C)alkyl or phenyl.

In another embodiment of the present invention there is provided acompound according to Formula I, which is designated as Formula I-a,wherein:

X is O;

Ring C is C-1

R³ is (1-6C)alkyl, hydroxy(1-6C)alkyl, Ar², hetCyc¹, (3-7C)cycloalkyl,or hetAr²;

R⁴ is H, OH, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluro(2-6C)alkyl, pentafluro(2-6C)alkyl,cyano(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3Calkoxy)(1-6C)alkyl, amino(1-6C)alkyl, aminocarbonyl(1-6C)alkyl,(1-3C)alkylsulfonamido(1-6C)alkyl, sulfamido(1-6C)alkyl,hydroxycarbonyl(1-6C)alkyl, hetAr³(1-6C)alkyl, Ar³(1-6C)alkyl,(1-6C)alkoxy, monofluoro(1-6C)alkoxy, difluoro(1-6C)alkoxytrifluoro(1-6C)alkoxy, tetrafluoro(2-6C)alkoxy, pentafluoro(2-6C)alkoxycyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy,amino(2-6C)alkoxy, hydroxyl-carbonyl(1-6C)alkoxy, hetCyc²(1-6C)alkoxy,hetAr³(1-6C)alkoxy, Ar³(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (1-3Calkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl [optionally substitutedwith F, OH, (1-6C alkyl), (1-6C) alkoxy, or (1-3C alkoxy)(1-6C)alkyl],hetAr⁴, hetAr⁴—O—, Ar⁴, hetCyc²(O)CH₂—, (1-4Calkoxycarbonyl)(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy,aminocarbonyl(1-6C)alkoxy, hetCyc²C(═O)(1-6C)alkoxy, hydroxy(1-3Calkoxy)(1-6C)alkoxy, hydroxytrifluoro(1-6C)alkoxy,(1-3C)alkylsulfonamido(1-6C)alkoxy, (1-3C)alkylamido(1-6C)alkoxy,di(1-3C alkyl)amino-carboxy, hetCyc²C(═O)O—, hydroxydifluoro(1-6C)alkyl,(1-4C alkylcarboxy)(1-6C)alkyl, (1-6C)alkoxycarbonyl, hydroxylcarbonyl,aminocarbonyl, (1-3C alkoxy)aminocarbonyl, hetCyc³, halogen, CN,trifluoromethylsulfonyl, N-(1-3C alkyl)oxadiazolonyl, or hetAr⁵;

R⁵ is (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl,halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3C alkoxy)(1-4C)alkyl,(1-4C alkyl)OC(═O)—, or phenyl optionally substituted with one or moregroups independently selected from halogen, (1-6C)alkyl and(1-6C)alkoxy; or

R⁴ and R⁵ together with the atoms to which they are attached form a 5-6membered saturated, partially unsaturated or unsaturated carbocyclicring optionally substituted with one or more substituents independentlyselected from (1-6C)alkyl, or

R⁴ and R⁵ together with the atoms to which they are attached form 5-6membered saturated, partially unsaturated or unsaturated heterocyclicring having a ring heteroatom selected from N, O or S, wherein saidheterocyclic ring is optionally substituted with one or two substituentsindependently selected from (1-6C alkyl)C(═O)O—, (1-6C)acyl, (1-6C)alkyland oxo, and said sulfur ring atom is optionally oxidized to S(═O) orSO₂;

and

Ring A, Y, R^(a), R^(b), R^(b), B, D, E, F, G, K, R^(l), R^(e), R,R^(g), R^(h), R^(i), R^(j), R^(k), R^(m), R^(m), R^(p), Ar², hetCyc¹,hetCyc², hetCyc³, hetAr³, Ar³, hetAr⁴ hetAr⁵, and Ar⁴ are as defined forFormula I.

In one embodiment of Formula I-a, R⁴ is (1-6C)alkoxy, hetAr⁴, Ar⁴ orhetAr⁵; and Ring A, Y, R^(a), R^(b), R^(b), B, D, E, F, G, K, RP, R³,R⁵, Ar², hetAr⁴, Ar⁴, and hetAr⁵ are as defined for Formula I.

In one embodiment of Formula I-a, Ring A is formula A-1; B is a bond orCR^(d)R^(e), D is a bond or CR^(f)R^(g), E is a bond or CR^(h)R^(i), andF is CR^(j)R^(k), wherein the ring formed by B, D, E, and F togetherwith the atoms to which they are attached contains 5-6 atoms, and Y,R^(a), R^(b), R^(b), R^(p), R³, R⁴, R⁵, Ar², hetAr⁴, Ar⁴, and hetAr⁵ areas defined for Formula I.

In one embodiment of Formula I-a, R³ is Ar²; R⁴ is (1-6C)alkoxy, hetAr⁴,Ar⁴ or hetAr⁵; R⁵ is (1-6C)alkyl; and Ring A, Y, R^(a), R^(b), R^(b), B,D, E, F, G, K, R¹, R^(f), R^(g), R^(h), R^(i), R^(j), R^(k), R^(m),R^(m), R^(p), Ar², hetAr⁴, Ar⁴, and hetAr⁵ are as defined for Formula I.In one embodiment, R³ is phenyl.

In one embodiment of Formula I-a, R³ is Ar²; R⁴ is (1-6C)alkoxy, hetAr⁴or hetAr⁵; R⁵ is (1-6C)alkyl; and Ring A, Y, R^(a), R^(b), R^(b), B, D,E, F, G, K, R^(l), R^(e), R, R^(g), R^(h), R^(i), R^(j), R^(k), R^(m),R^(m), R^(p), Ar², hetAr⁴, and hetAr⁵ are as defined for Formula I. Inone embodiment, R³ is phenyl.

In one embodiment of Formula I-a, R³ is Ar²; R⁴ is (1-6C)alkoxy orhetAr⁵; R⁵ is (1-6C)alkyl; and Ring A, Y, R^(a), R^(b), R^(b), B, D, E,F, G, K, R¹, R^(f), R^(g), R^(h), R^(i), R^(j), R^(k), R^(m), R^(m),R^(p), Ar², hetAr⁵ and Ar⁴ are as defined for Formula I. In oneembodiment, R³ is phenyl.

In one embodiment of Formula I-a, R³ is Ar²; R⁴ is (1-6C)alkoxy orhetAr⁴; R⁵ is (1-6C)alkyl; Ring A is formula A-1; and Y, R^(a), R^(b),R^(b), B, D, E, F, R^(l), R^(e), R^(f), R^(g), R^(h), R^(i), R, R^(k),Ar², hetAr⁴ and Ar⁴ are as defined for Formula I. In one embodiment, R³is phenyl.

In one embodiment of Formula I-a, R³ is Ar²; R⁴ is (1-6C)alkoxy orhetAr⁴; R⁵ is (1-6C)alkyl; Y is H; Ring A is formula A-1; B is a bond orCR^(d)R^(e), D is a bond or CR^(f)R^(g), E is a bond or CR^(h)R^(i), andF is CR^(j)R^(k), wherein the ring formed by B, D, E, and F togetherwith the atoms to which they are attached contains 5-6 atoms, and R^(a),R^(b), R^(b), R¹, R^(f), R^(g), R^(h), R^(i), R^(j), R^(k), Ar², hetAr⁴and Ar⁴ are as defined for Formula I. In one embodiment, R³ is phenyl.

In one embodiment of Formula I-a, R³ is Ar²; R⁴ is (1-6C)alkoxy, hetAr⁴or hetAr⁵; R⁵ is halogen or (1-6C)alkyl; Ring A is formula A-2; and Y,R^(a), R^(b), R^(b), G, K, R^(l), R^(m), R^(n), R^(p), Ar², hetAr⁴, andhetAr⁵ are as defined for Formula I. In one embodiment, R³ is phenyl.

In another embodiment of the present invention there is provided acompound according to Formula I, which is designated as Formula I-b,wherein:

X is O;

Ring A is formula A-1:

B is a bond or CR^(d)R^(e),

D is a bond or CR^(f)R^(g),

E is a bond or CR^(h)R^(i), and

F is CR^(j)R^(k),

provided that the ring formed by B, D, E, and F together with the atomsto which they are attached contains at least five atoms;

zero to four of R^(d), R^(e), R^(f), R^(g), R^(h), R^(i), R^(j) andR^(k) are independently OH, (1-6C)alkyl [optionally substituted with oneto five fluoros], (3-6C)cycloalkyl [optionally substituted with one tofive fluoros], (1-3C alkoxy)(2-6C)alkyl [optionally substituted with oneto five fluoros], (1-6C)alkoxy [optionally substituted with one to fivefluoros], or (1-3C alkoxy)(2-6C)alkoxy [optionally substituted with oneto five fluoros],

or one of a pair of R^(d) and R^(e), or R^(f) and R^(g), or R^(h) andR^(i), or R^(j) and R^(k), together with the carbon atom to which theyare attached form a (3-6C)cycloalkyl, oxetanyl or azetidinyl ring, orone of a pair of R^(d) and R^(e), or R^(f) and R^(g), or R^(h) andR^(i), or R^(j) and R^(k) form an oxo group, and the remainder arehydrogen,

and wherein only one of R^(d) and R^(e) can be OH and neither is OH if Bis connected to a heteroatom, and only one of R^(f) and R^(g) can be OHand neither is OH if D is connected to a heteroatom, and only one ofR^(h) and R^(i) can be OH and neither is OH if E is connected to aheteroatom, and only one of R^(j) and R^(k) can be OH and neither is OHif F is connected to a heteroatom;

and R^(a), R^(b), R^(c), Y and Ring C are as defined for Formula I. In afurther embodiment of Formula I-b, Ring C is C-1. In a furtherembodiment of Formula I-b, R⁴ is (1-6C)alkoxy, hetAr⁴ or hetAr⁵. In afurther embodiment of Formula I-b, R³ is Ar². In a further embodiment ofFormula I-b, R⁵ is halogen or (1-6C)alkyl. In a further embodiment ofFormula I-b, Y is H, halogen, or (1-3C alkoxy)(1-6C)alkyl. In a furtherembodiment of Formula I-b, R³ is phenyl.

In another embodiment of the present invention there is provided acompound according to Formula I, which is designated as Formula I-c,wherein:

X is O;

B is O, a bond or CR^(d)R^(e),

D is O, a bond or CR^(f)R^(g),

E is O, a bond or CR^(h)R^(i), and

F is CR^(j)R^(k),

provided that the ring formed by B, D, E, and F together with the atomsto which they are attached contains at least five atoms and contains oneoxygen atom;

zero to four of R^(d), R^(e), R^(f), R^(g), R^(h), R^(i), R^(j) andR^(k) are independently OH, (1-6C)alkyl [optionally substituted with oneto five fluoros], (3-6C)cycloalkyl [optionally substituted with one tofive fluoros], (1-3C alkoxy)(2-6C)alkyl [optionally substituted with oneto five fluoros], (1-6C)alkoxy [optionally substituted with one to fivefluoros], or (1-3C alkoxy)(2-6C)alkoxy [optionally substituted with oneto five fluoros],

or one of a pair of R^(d) and R^(e), or R^(f) and R^(g), or R^(h) andR^(i), or R^(j) and R^(k), together with the carbon atom to which theyare attached form a (3-6C)cycloalkyl, oxetanyl or azetidinyl ring, orone of a pair of R^(d) and R^(e), or R^(f) and R^(g), or R^(h) andR^(i), or R^(j) and R^(k) form an oxo group, and the remainder arehydrogen,

and wherein only one of R^(d) and R^(e) can be OH and neither is OH if Bis connected to a heteroatom, and only one of R^(f) and R^(g) can be OHand neither is OH if D is connected to a heteroatom, and only one ofR^(h) and R^(i) can be OH and neither is OH if E is connected to aheteroatom, and only one of R^(j) and R^(k) can be OH and neither is OHif F is connected to a heteroatom;

and R^(a), R^(b), R^(c), Y and Ring C are as defined for Formula I. Inone embodiment, B is O, D is a bond or CR^(f)R^(g), and E is a bond orCR^(h)R^(i). In one embodiment, B is a bond or CR^(d)R^(e), D is O, andE is a bond or CR^(h)R^(i). In one embodiment, B is a bond orCR^(d)R^(e), D is a bond or CR^(f)R^(g), and E is O. In a furtherembodiment of Formula I-c, R⁴ is (1-6C)alkoxy, hetAr⁴ or hetAr⁵. In afurther embodiment of Formula I-c, R³ is Ar². In a further embodiment ofFormula I-c, R⁵ is halogen or (1-6C)alkyl. In a further embodiment ofFormula I-c, Y is H, halogen or (1-3C alkoxy)(1-6C)alkyl. In a furtherembodiment of Formula I-c, R³ is phenyl.

In another embodiment of the present invention there is provided acompound according to Formula I, which is designated as Formula I-d,wherein:

X is O;

B is NR¹, a bond or CR^(d)R^(e),

D is NR¹, a bond or CR^(f)R^(g),

E is NR¹, a bond or CR^(h)R^(i),

F is CR^(j)R^(k),

provided that the ring formed by B, D, E, and F together with the atomsto which they are attached contains at least five atoms and contains onenitrogen atom;

zero to four of R^(d), R^(e), R^(f), R^(g), R^(h), R^(i), R^(j) andR^(k) are independently OH, (1-6C)alkyl [optionally substituted with oneto five fluoros], (3-6C)cycloalkyl [optionally substituted with one tofive fluoros], (1-3C alkoxy)(2-6C)alkyl [optionally substituted with oneto five fluoros], (1-6C)alkoxy [optionally substituted with one to fivefluoros], or (1-3C alkoxy)(2-6C)alkoxy [optionally substituted with oneto five fluoros],

or one of a pair of R^(d) and R^(e), or R^(f) and R^(g), or R^(h) andR^(i), or R^(j) and R^(k), together with the carbon atom to which theyare attached form a (3-6C)cycloalkyl, oxetanyl or azetidinyl ring, orone of a pair of R^(d) and R^(e), or R^(f) and R^(g), or R^(h) andR^(i), or R^(j) and R^(k) form an oxo group, and the remainder arehydrogen,

and wherein only one of R^(d) and R^(e) can be OH and neither is OH if Bis connected to a heteroatom, and only one of R^(f) and R^(g) can be OHand neither is OH if D is connected to a heteroatom, and only one ofR^(h) and R^(i) can be OH and neither is OH if E is connected to aheteroatom, and only one of R^(j) and R^(k) can be OH and neither is OHif F is connected to a heteroatom;

and R¹, R^(a), R^(b), R^(c), Y and Ring C are as defined for Formula I.In one embodiment, B is NR¹, D is a bond or CR^(f)R^(g), and E is a bondor CR^(h)R^(i). In one embodiment, B is a bond or CR^(d)R^(e), D is NR¹,and E is a bond or CR^(h)R^(i). In one embodiment, B is a bond orCR^(d)R^(e), D is a bond or CR^(f)R^(g), and E is NR¹. In a furtherembodiment of Formula I-d, R⁴ is (1-6C)alkoxy, hetAr⁴ or hetAr⁵. In afurther embodiment of Formula I-d, R³ is Ar². In a further embodiment ofFormula I-d, R⁵ is halogen or (1-6C)alkyl. In a further embodiment ofFormula I-d, Y is H, halogen or (1-3C alkoxy)(1-6C)alkyl. In a furtherembodiment of Formula I-d, R³ is phenyl.

In another embodiment of the present invention there is provided acompound according to Formula I, which is designated as Formula I-e,wherein:

X is O;

Ring A is formula A-2;

and G, K, Y, R^(l), R^(m), R^(n), RP, and Ring C are as defined forFormula I. In a further embodiment of Formula I-e, Ring C is C-1. In afurther embodiment of Formula I-e, R⁴ is (1-6C)alkoxy, hetAr⁴ or hetAr⁵,and R³ and R⁵ are as defined for Formula I. In a further embodiment ofFormula I-e, R³ is Ar², and R⁵ is as defined for Formula I. In a furtherembodiment of Formula I-e, R⁵ is (1-6C)alkyl. In a further embodiment ofFormula I-e, R^(p) is H. In a further embodiment of Formula I-e, Y is H,halogen or (1-3C alkoxy)(1-6C)alkyl. In a further embodiment of FormulaI-e, R³ is phenyl.

In another embodiment of the present invention there is provided acompound according to Formula I, which is designated as Formula I-f,wherein:

X is O;

Ring A is formula A-2;

B is NR¹ or O, D is a bond or CR^(f)R^(g), E is a bond or CR^(h)R^(i),and F is CR^(j)R^(k), provided that the ring formed by B, D, E, and Ftogether with the atoms to which they are attached contains at leastfive atoms;

zero to four of R^(d), R^(e), R^(f), R^(g), R^(h), R^(i), R^(j) andR^(k) are independently OH, (1-6C)alkyl [optionally substituted with oneto five fluoros], (3-6C)cycloalkyl [optionally substituted with one tofive fluoros], (1-3C alkoxy)(2-6C)alkyl [optionally substituted with oneto five fluoros], (1-6C)alkoxy [optionally substituted with one to fivefluoros], or (1-3C alkoxy)(2-6C)alkoxy [optionally substituted with oneto five fluoros],

or one of a pair of R^(d) and R^(e), or R^(f) and R^(g), or R^(h) andR^(i), or R^(j) and R^(k), together with the carbon atom to which theyare attached form a (3-6C)cycloalkyl, oxetanyl or azetidinyl ring, orone of a pair of R^(d) and R^(e), or R^(f) and R^(g), or R^(h) andR^(i), or R^(j) and R^(k) form an oxo group, and the remainder arehydrogen,

and wherein only one of R^(d) and R^(e) can be OH and neither is OH if Bis connected to a heteroatom, and only one of R^(f) and R^(g) can be OHand neither is OH if D is connected to a heteroatom, and only one ofR^(h) and R^(i) can be OH and neither is OH if E is connected to aheteroatom, and only one of R^(j) and R^(k) can be OH and neither is OHif F is connected to a heteroatom;

and R¹, R^(a), R^(b), R^(c), Y and Ring C are as defined for Formula I.In a further embodiment of Formula I-f, R⁴ is (1-6C)alkoxy, hetAr⁴ orhetAr⁵. In a further embodiment of Formula I-f, R³ is Ar². In a furtherembodiment of Formula I-f, R⁵ is halogen or (1-6C)alkyl. In a furtherembodiment of Formula I-f, Y is H, halogen or (1-3C alkoxy)(1-6C)alkyl.In a further embodiment of Formula I-f, R³ is phenyl.

In another embodiment of the present invention there is provided acompound according to Formula I, which is designated as Formula I-g,wherein:

X is O;

Ring A is formula A-2;

B is a bond or CR^(d)R^(e); D is NR¹ or O, E is a bond or CR^(h)R^(i),and F is CR^(j)R^(k), provided that the ring formed by B, D, E, and Ftogether with the atoms to which they are attached contains at leastfive atoms;

zero to four of R^(d), R^(e), R^(f), R^(g), R^(h), R^(i), R^(j) andR^(k) are independently OH, (1-6C)alkyl [optionally substituted with oneto five fluoros], (3-6C)cycloalkyl [optionally substituted with one tofive fluoros], (1-3C alkoxy)(2-6C)alkyl [optionally substituted with oneto five fluoros], (1-6C)alkoxy [optionally substituted with one to fivefluoros], or (1-3C alkoxy)(2-6C)alkoxy [optionally substituted with oneto five fluoros],

or one of a pair of R^(d) and R^(e), or R^(f) and R^(g), or R^(h) andR^(i), or R^(j) and R^(k), together with the carbon atom to which theyare attached form a (3-6C)cycloalkyl, oxetanyl or azetidinyl ring, orone of a pair of R^(d) and R^(e), or R^(f) and R^(g), or R^(h) andR^(i), or R^(j) and R^(k) form an oxo group, and the remainder arehydrogen,

and wherein only one of R^(d) and R^(e) can be OH and neither is OH if Bis connected to a heteroatom, and only one of R^(f) and R^(g) can be OHand neither is OH if D is connected to a heteroatom, and only one ofR^(h) and R^(i) can be OH and neither is OH if E is connected to aheteroatom, and only one of R^(j) and R^(k) can be OH and neither is OHif F is connected to a heteroatom;

and R¹, R^(a), R^(b), R^(c), Y and Ring C are as defined for Formula I.In a further embodiment of Formula I-g, R⁴ is (1-6C)alkoxy, hetAr⁴ orhetAr⁵. In a further embodiment of Formula I-g, R³ is Ar². In a furtherembodiment of Formula I-g, R⁵ is halogen or (1-6C)alkyl. In a furtherembodiment of Formula I-g, Y is H, halogen or (1-3C alkoxy)(1-6C)alkyl.In a further embodiment of Formula I-g, R³ is phenyl.

It will be appreciated that certain compounds according to the inventionmay contain one or more centers of asymmetry and may therefore beprepared and isolated in a mixture of isomers such as a racemic mixture,or in an enantiomerically pure form.

It will further be appreciated that the compounds of Formula I or theirsalts may be isolated in the form of solvates, and accordingly that anysuch solvate is included within the scope of the present invention. Forexample, compounds of Formula I can exist in unsolvated as well assolvated forms with pharmaceutically acceptable solvents such as water,ethanol, and the like.

The compounds of Formula I include pharmaceutically acceptable saltsthereof. In addition, the compounds of Formula I also include othersalts of such compounds which are not necessarily pharmaceuticallyacceptable salts, and which are useful as intermediates for preparingand/or purifying compounds of Formula I and/or for separatingenantiomers of compounds of Formula I. Particular examples of saltsinclude hydrochloride salts or trifluoroacetate salts.

In one embodiment, the compounds of Formula I include the free base formof compounds of Examples 1-160, or pharmaceutically acceptable saltsthereof.

In one embodiment, the compounds of Formula I include the hydrochloridesalts of compounds of Examples 1-160.

In one embodiment, the compounds of Formula I include thetrifluoroacetate salts of compounds of Examples 1-160.

The term “pharmaceutically acceptable” indicates that the substance orcomposition is compatible chemically and/or toxicologically, with theother ingredients comprising a formulation, and/or the mammal beingtreated therewith.

The present invention also provides a process for the preparation of acompound of Formula I or a salt thereof as defined herein, whichcomprises:

(a) for a compound of Formula I where X is O, coupling a correspondingcompound having the formula II

with a corresponding compound having the formula III

in the presence carbonyldiimidazole or triphosgene and a base; or

(b) for a compound of Formula I where X is S, coupling a correspondingcompound having the formula II

with a corresponding compound having the formula III

in the presence di(1H-imidazol-2-yl)methanethione and a base; or

(c) for a compound of Formula I where X is O, coupling a correspondingcompound having the formula II

with a corresponding compound having the formula IV

where L¹ is a leaving group, in the presence of a base; or

(d) for a compound of Formula I where X is O, coupling a correspondingcompound having the formula V

where L² is a leaving group, with a corresponding compound having theformula III

in the presence of a base; or

(e) for a compound of Formula I where X is O, activating a correspondingcompound having the formula VI

with diphenylphosphoryl azide followed by coupling the activatedintermediate with a corresponding compound having the formula III

in the presence of a base; or

(f) for a compound of Formula I where X is O, coupling a correspondingcompound having the formula II

with a corresponding compound having the formula VII

in the presence of a base; or

(g) for a compound of Formula I where X is O, coupling a correspondingcompound having the formula VIII

with a corresponding compound having the formula III

in the presence of a base; and

optionally removing protecting groups and optionally preparing apharmaceutically acceptable salt thereof.

In the above methods, the term “corresponding” means that thedefinitions for the “corresponding compound” are as defined for FormulaI unless stated otherwise.

Referring to method (a), the base may be an amine base, such astriethylamine or diisopropylethylamine. Suitable solvents includedichloromethane, dichloroethane, THF, DMA and DMF. The reaction isconveniently performed at ambient temperature.

Referring to method (b), the base may be an amine base, such astriethylamine or diisopropylethylamine. Suitable solvents includedichloromethane, dichloroethane, THF, DMA and DMF. The reaction isconveniently performed at ambient temperature.

Referring to method (c), the leaving group may be, for example, phenoxyor 4-nitrophenoxy. The base may be an amine base, such as triethylamineor diisopropylethylamine. Suitable solvents include DMA, DMF and DCE.The reaction is conveniently performed at ambient temperature.

Referring to method (d), the leaving group may be, for example, phenoxyor 4-nitrophenoxy. The base may be an amine base, such as triethylamineor diisopropylethylamine. Suitable solvents include DCE, DMA and DMF.The reaction is conveniently performed at ambient temperature.

Referring to method (e), the base may be an amine base, such astriethylamine or diisopropylethylamine. Suitable solvents includetoluene and DMF. The reaction is conveniently performed at elevatedtemperatures, for example the reflux temperature of the solvent.

Referring to methods (f) and (g), the base may be an amine base, such astriethylamine or diisopropylethylamine. Suitable solvents include DCM,DCE, DMF and THF. The reaction is conveniently performed at temperaturesbetween about 0° C. and ambient temperature.

Amine groups in compounds described in any of the above methods may beprotected with any convenient amine protecting group, for example asdescribed in Greene & Wuts, eds., “Protecting Groups in OrganicSynthesis”, 2^(nd) ed. New York; John Wiley & Sons, Inc., 1991. Examplesof amine protecting groups include acyl and alkoxycarbonyl groups, suchas t-butoxycarbonyl (BOC), benzyloxycarbonyl (Cbz), and[2-(trimethylsilyl)ethoxy]methyl (SEM). Likewise, carboxyl groups may beprotected with any convenient carboxyl protecting group, for example asdescribed in Greene & Wuts, eds., “Protecting Groups in OrganicSynthesis”, 2^(nd) ed. New York; John Wiley & Sons, Inc., 1991. Examplesof carboxyl protecting groups include (1-6C)alkyl groups, such asmethyl, ethyl and t-butyl. Alcohol groups may be protected with anyconvenient alcohol protecting group, for example as described in Greene& Wuts, eds., “Protecting Groups in Organic Synthesis”, 2^(nd) ed. NewYork; John Wiley & Sons, Inc., 1991. Examples of alcohol protectinggroups include acetyl, benzyl, trityl, silyl ethers, and the like.

The compounds of the formulas II, III, IV, V, VI, VII and VIII are alsoprovided as further aspects of the invention. In one embodiment, thecompounds of the formulas II, III, IV, V, VI, VII and VIII are useful asintermediates for the preparation of compounds of Formula I.

Compounds of Formula I are useful in the treatment of pain, cancer,inflammation/inflammatory diseases, neurodegenerative diseases, certaininfectious diseases, Sjogren's syndrome, endometriosis, diabeticperipheral neuropathy, prostatitis or pelvic pain syndrome.

In one embodiment, compounds of Formula I are useful for treating pain,including chronic and acute pain. For example, compounds of Formula Iare useful in the treatment of multiple types of pain includinginflammatory pain, neuropathic pain, and pain associated with cancer,surgery or bone fracture.

In one embodiment, compounds of Formula I are useful for treating acutepain. Acute pain, as defined by the International Association for theStudy of Pain, results from disease, inflammation, or injury to tissues.This type of pain generally comes on suddenly, for example, after traumaor surgery, and may be accompanied by anxiety or stress, and is confinedto a given period of time and severity. In some instances, it can becomechronic.

In one embodiment, compounds of Formula I are useful for treatingchronic pain. Chronic pain, as defined by the International Associationfor the Study of Pain, is widely believed to represent a disease initself. It can be made much worse by environmental and psychologicalfactors. Chronic pain persists over a longer period than acute pain andis resistant to most medical treatments, generally over 3 months ormore. It can and often does cause severe problems for patients.

Compounds of Formula I are also useful for treating cancer. Particularexamples include neuroblastoma, ovarian, pancreatic, colorectal andprostate cancer.

Compounds of Formula I are also useful for treating inflammation andcertain infectious diseases. For example, compounds of Formula I may beused to treat interstitial cystitis (IC), painful bladder syndrome(PBS), urinary incontinence, asthma, atopic dermatitis, and psoriasis.

Compounds of Formula I are also useful for treating a neurodegenerativedisease in a mammal, comprising administering to said mammal one or morecompounds of Formula I or a pharmaceutically acceptable salt thereof inan amount effective to treat said neurodegenerative disease. In oneembodiment, compounds of Formula I may also be used to treatdemyelination and dysmyelination by promoting myelination, neuronalsurvival, and oligodendrocyte differentiation via blocking Sp35-TrkAinteraction. In one embodiment, the neurodegenerative disease ismultiple sclerosis. In one embodiment, the neurodegenerative disease isParkinson's disease. In one embodiment, the neurodegenerative disease isAlzheimer's disease.

Compounds of Formula I are also useful for treating certain infectiousdiseases such as Trypanosoma cruzi infection in a mammal.

Compounds of Formula I are also useful for treating Sjogren's syndromein a mammal.

Compounds of Formula I are also useful for treating endometriosis in amammal.

Compounds of Formula I are also useful for treating diabetic peripheralneuropathy in a mammal.

Compounds of Formula I are also useful for treating prostatitis in amammal.

Compounds of Formula I are also useful for treating pelvic pain syndromein a mammal.

Compounds of Formula I are also useful in treating diseases related toan imbalance of the regulation of bone remodeling, such as osteoporosis,rheumatoid arthritis, and bone metastases.

As used herein, terms “treat” or “treatment” refer to therapeutic orpalliative measures. Beneficial or desired clinical results include, butare not limited to, alleviation, in whole or in part, of symptomsassociated with a disorder or condition, diminishment of extent ofdisease, stabilized (i.e., not worsening) state of disease, delay orslowing of disease progression, amelioration or palliation of thedisease state, and remission (whether partial or total), whetherdetectable or undetectable. “Treatment” can also mean prolongingsurvival as compared to expected survival if not receiving treatment.

In certain embodiments, compounds of Formula I are useful for preventingdiseases and disorders as defined herein. The term “preventing” as usedherein means the prevention of the onset, recurrence or spread, in wholeor in part, of the disease or condition as described herein, or asymptom thereof, and includes to the administration of a compound ofFormula I prior to the onset of symptoms.

Accordingly, one embodiment of this invention provides a method oftreating pain in a mammal, comprising administering to said mammal inneed thereof one or more compounds of Formula I or a pharmaceuticallyacceptable salt thereof in an amount effective to treat said pain. Inone embodiment, the pain is chronic pain. In one embodiment, the pain isacute pain. In one embodiment, the pain is inflammatory pain,neuropathic pain, or pain associated with cancer, surgery, or bonefracture.

Another embodiment of this invention provides a method of preventingpain in a mammal, comprising administering to said mammal in needthereof one or more compounds of Formula I or a pharmaceuticallyacceptable salt thereof in an amount effective to prevent said pain. Inone embodiment, the pain is chronic pain. In one embodiment, the pain isacute pain. In one embodiment, the pain is inflammatory pain,neuropathic pain, or pain associated with cancer, surgery, or bonefracture.

Another embodiment of this invention provides a method of treatingcancer in a mammal, comprising administering to said mammal in needthereof one or more compounds of Formula I or a pharmaceuticallyacceptable salt thereof in an amount effective to treat said cancer.

In one embodiment, provided herein is a method for treating a patientdiagnosed with a cancer having a dysregulation of TrkA, comprisingadministering to the patient a therapeutically effective amount of acompound of the invention or a pharmaceutically acceptable salt thereof.

In one embodiment, the dysregulation of TrkA comprises overexpression ofwild-type TrkA (autocrine activation).

In one embodiment, the dysregulation of TrkA comprises one or morechromosome translocations or inversions resulting in TrkA gene fusions.In one embodiment, the dysregulation is a result of genetictranslocations in which the expressed protein is a fusion proteincontaining residues from non-TrkA and TrkA proteins, and at a minimumthe TrkA kinase domain. In one embodiment, the TrkA fusion protein isLMNA-TrkA, TFG-TrkA, TPM3-TrkA, CD74-TrkA, NFASC-TrkA, MPRIP-TrkA,BCAN-TrkA, or TPR-TrkA, where:

LMNA=Prelamin-A/C;

TFG=TRK-fused gene protein;

TPM3=Tropomysin alpha-3;

CD74=HLA class II histocompatibility antigen gamma chain;

NFASC=Neurofascin;

MPRIP=MPRIP protein;

BCAN=Brevican core protein; and

TPR=Nucleoprotein TPR

In one embodiment, the dysregulation of TrkA comprises one or moredeletions, insertions or mutations in the TrkA protein. In oneembodiment, the dysregulation comprises a deletion of one or moreresidues from the TrkA protein, resulting in constitutive activity ofTrkA kinase. In one embodiment the deletion includes deletion ofresidues 303-377 in TrkA Isoform 2.

In one embodiment, the dysregulation of TrkA comprises a splicevariation in which the expressed protein is an alternatively splicedvariant of TrkA having one or more residues deleted resulting inconstitutive activity of TrkA kinase. In one embodiment, analternatively spliced form of TrkA with constitutive activity hasdeletions of exons 8, 9, and 11 resulting in an expressed proteinmissing residues 192-284 and 393-398 relative to TrkA Isoform 2.

Cancers identified as having dysregulation of TrkA (see literaturereferences below; also see www.cancer.gov and www.nccn.org) include:

(A) Cancers wherein the dysregulation of TrkA comprises one or morechromosome translocations or inversions resulting in TrkA gene fusions,including:

Cancer Literature reference(s) Standard of Care Non-Small Cell Vaishnaviet al. 2013: radiotherapy (e.g. radioiodide therapy, Lung Cancer NatureMedicine 19, external-beam radiation, radium 223 1469-1472 therapy),chemotherapeutics as single agents (e.g. afatinib dimaleate,bevacizumab, carboplatin, cetuximab, cisplatin, crizotinib, erlotinib,gefitinib, gemcitabine, methotrexate, paclitaxel, pemetrexed) orcombinations (e.g. carboplatin-paclitaxel, gemcitabine- paclitaxel,chemoradiation) Papillary Thyroid Caria et al. 2010: CancerRadiotherapies (e.g. radioiodide therapy, Carcinoma Genetics andexternal-beam radiation) and Cytogenetics 203: 21-29 chemotherapeutics(e.g. sorafenib, sunitinib, pazopanib) Glioblastoma Frattini et al.2013: Chemotherapeutics (e.g. bevacizumab, Multiforme Nature Genet.everolimus, lomustine, temozolomide) 45(10): 1141-9 ColorectalMartin-Zanca et al. Chemotherapeutics as single agents Carcinoma 1986:Nature 319: 743 (aflibercept, bevacizumab, capecitabine, cetuximab,fluorouracil, irinotecan, leucovorin, oxaliplatin, panitumumab,regorafenib) or combinations (e.g. folfox, folfiri, capox,folfiri-bevacizumab, folfiri- cetuximab, xelox) Melanoma WO 2013/059740A1 Chemotherapeutics (e.g. aldesleukin, dabrafenib, dacarbazine,interferon alfa- 2b, ipilimumab, peginterferon alfa-2b, trametinib,vemurafenib)

(B) Cancers wherein the dysregulation of TrkA comprises one or moredeletions, insertions or mutations in the TrkA protein, including:

Cancer Literature reference(s) Standard of care Acute Myeloid Meyer2007: Leukemia 21: Chemotherapeutics as single leukemia 2171-2180 agents(e.g. arsenic trioxide, Reuther et al. 2000: Mol Cell cyclophosphamide,cytarabine, Biol 20: 8655-8666 daunorubicin, doxorubicin, vincristine)or combinations (e.g. ADE) Large Cell Marchetti et al 2008: HumanRadiotherapy (e.g. radioiodide Neuroendocrine Mutation 29(5): 609-616therapy, external-beam radiation, Carcinoma radium 223 therapy) and/orchemotherapeutics (e.g. cisplatin, carboplatin, etoposide) NeuroblastomaTacconelli et al 2004: Cancer Chemotherapeutics (e.g. Cell 6: 347cyclophosphamide, doxorubicin, vincristine)

(C) Cancers driven by overexpression of wild-type TrkA (autocrineactivation), including:

Cancer Literature Reference(s) Standard of care Prostate Carcinoma Walchet al: Clinical & Radiotherapy (e.g. radium 223 Experimental Metastasis17: 307-314 therapy) or chemotherapeutics Papatsoris et al 2007: Expert(e.g. abiraterone, cabazitaxel, Opinion on Investigational Drugsdegarelix, denosumab, docetaxel, 16(3): 303-309 enzalutamide,leuprolide, prednisone, sipuleucel-T) Neuroblastoma Van Noesel et al2004: Gene 325: Chemotherapeutics (e.g. 1-15 cyclophosphamide,doxorubicin, vincristine) Pancreatic Zhang et al 2005: OncologyChemotherapeutics as single Carcinoma Reports 14: 161-171 agents (e.g.erlotinib, fluorouracil, gemcitabine, mitomycin C) or combinations (e.g.gemcitabine- oxaliplatin) Melanoma Truzzi et al 2008: Journal ofChemotherapeutics (e.g. Investigative Dermatology 128(8): aldesleukin,dabrafenib, 2031 dacarbazine, interferon alfa-2b, ipilimumab,peginterferon alfa-2b, trametinib, vemurafenib) Head and Neck Kolokythaset al 2010: Journal of Radiotherapy and/or Squamous Cell Oral andMaxillofacial Surgery chemotherapeutics (e.g. Carcinoma 68(6): 1290-1295bleomycin, cetuximab, cisplatin, docetaxel, fluorouracil, methotrexate)Gastric Carcinoma Ni et al 2012: Asian Pacific Chemotherapeutics (e.g.Journal of Cancer Prevention 13: docetaxel, doxorubucin, 1511fluorouracil, mitomycin C, trastuzumab)

In one embodiment, provided herein is a method for treating a patientdiagnosed with a cancer having a dysregulation of TrkA, comprisingadministering to the patient a therapeutically effective amount of acompound of the invention, or a pharmaceutically acceptable saltthereof, wherein the cancer is selected from non-small cell lung cancer,papillary thyroid carcinoma, glioblastoma multiforme, acute myeloidleukemia, colorectal carcinoma, large cell neuroendocrine carcinoma,prostate cancer, neuroblastoma, pancreatic carcinoma, melanoma, head andneck squamous cell carcinoma and gastric carcinoma.

In one embodiment, the compounds of the present invention are useful fortreating cancer in combination with one or more additional therapeuticagents or therapies that work by the same or a different mechanism ofaction.

In one embodiment, the additional therapeutic agent(s) is selected fromreceptor tyrosine kinase-targeted therapeutic agents, includingcabozantinib, crizotinib, erlotinib, gefitinib, imatinib, lapatinib,nilotinib, pazopanib, pertuzumab, regorafenib, sunitinib, andtrastuzumab.

In one embodiment, the additional therapeutic agent(s) is selected fromsignal transduction pathway inhibitors, including Ras-Raf-MEK-ERKpathway inhibitors (e.g. sorafenib, trametinib, vemurafenib),PI3K-Akt-mTOR-S6K pathway inhibitors (e.g. everolimus, rapamycin,perifosine, temsirolimus) and modulators of the apoptosis pathway (e.g.obataclax).

In one embodiment, the additional therapeutic agent(s) is selected fromcytotoxic chemotherapeutics, including arsenic trioxide, bleomycin,cabazitaxel, capecitabine, carboplatin, cisplatin, cyclophosphamide,cytarabine, dacarbazine, daunorubicin, docetaxel, doxorubicin,etoposide, fluorouracil, gemcitabine, irinotecan, lomustine,methotrexate, mitomycin C, oxaliplatin, paclitaxel, pemetrexed,temozolomide, and vincristine.

In one embodiment, the additional therapeutic agent(s) is selected fromangiogenesis-targeted therapies, including aflibercept and bevacizumab.

In one embodiment, the additional therapeutic agent(s) is selected fromimmune-targeted agents, including aldesleukin, ipilimumab,lambrolizumab, nivolumab, sipuleucel-T.

In one embodiment, the additional therapeutic agent(s) is selected fromagents active against the TrkA pathway, including NGF-targetedbiopharmaceuticals such as NGF antibodies, and panTrk inhibitors.

In one embodiment, the additional therapeutic agent or therapy isradiotherapy, including radioiodide therapy, external-beam radiation andradium 223 therapy.

In one embodiment, the additional therapeutic agent(s) includes any oneof the above listed therapies or therapeutic agents which are standardsof care in cancers wherein the cancer has a dysregulation of TrkA.

In one embodiment, provided herein is a method of treating cancer in apatient, comprising administering to said patient a compound of theinvention or a pharmaceutically acceptable salt thereof, in combinationwith at least one additional therapy or therapeutic agent selected fromradiotherapy (e.g. radioiodide therapy, external-beam radiation, radium223 therapy), cytotoxic chemotherapeutics (e.g. arsenic trioxide,bleomycin, cabazitaxel, capecitabine, carboplatin, cisplatin,cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel,doxorubicin, etoposide, fluorouracil, gemcitabine, irinotecan,lomustine, methotrexate, mitomycin C, oxaliplatin, paclitaxel,pemetrexed, temozolomide, vincristine), tyrosine kinasetargeted-therapeutics (e.g. afatinib, cabozantinib, cetuximab,crizotinib, dabrafenib, erlotinib, gefitinib, imatinib, lapatinib,nilotinib, pazopanib, panitumumab, pertuzumab, regorafenib, sunitinib,trastuzumab), apoptosis modulators and signal transduction inhibitors(e.g. everolimus, perifosine, rapamycin, sorafenib, temsirolimus,trametinib, vemurafenib), immune-targeted therapies (e.g. aldesleukin,interferon alfa-2b, ipilimumab, lambrolizumab, nivolumab, prednisone,sipuleucel-T) and angiogenesis-targeted therapies (e.g. aflibercept,bevacizumab), wherein the amount of the compound of the invention or apharmaceutically acceptable salt thereof is, in combination with theadditional therapy or therapeutic agent, is effective in treating saidcancer. These additional therapeutic agents may be administered with oneor more compounds of the invention as part of the same or separatedosage forms, via the same or different routes of administration, and onthe same or different administration schedules according to standardpharmaceutical practice known to one skilled in the art.

Also provided herein is (i) a pharmaceutical combination for treatingcancer in a patient in need thereof, which comprises (a) a compound ofthe invention or a pharmaceutically acceptable salt thereof, (b) anadditional therapeutic agent and (c) optionally at least onepharmaceutically acceptable carrier for simultaneous, separate orsequential use for the treatment of a tumor disease, wherein the amountsof the compound or salt thereof and of the additional therapeutic agentare together effective in treating said cancer; (ii) a pharmaceuticalcomposition comprising such a combination; (iii) the use of such acombination for the preparation of a medicament for the treatment ofcancer; and (iv) a commercial package or product comprising such acombination as a combined preparation for simultaneous, separate orsequential use; and to a method of treatment of cancer a patient in needthereof.

In one embodiment, the combination therapy is for treating a cancer isselected from non-small cell lung cancer, papillary thyroid carcinoma,glioblastoma multiforme, acute myeloid leukemia, colorectal carcinoma,large cell neuroendocrine carcinoma, prostate cancer, neuroblastoma,pancreatic carcinoma, melanoma, head and neck squamous cell carcinomaand gastric carcinoma.

Another embodiment of this invention provides a method of treatinginflammation or an inflammatory disease or disorder in a mammal,comprising administering to said mammal in need thereof one or morecompounds of Formula I or a pharmaceutically acceptable salt thereof inan amount effective to treat said inflammation. In one embodiment, theinflammatory disease is inflammatory lung diseases (such as asthma),interstitial cystitis, bladder pain syndrome, inflammatory boweldiseases (including ulcerative colitis and Crohn's disease), andinflammatory skin diseases such as atopic dermatitis.

In one embodiment, the method of treating inflammation or aninflammatory disease or disorder comprises administering a compound ofthe invention in combination with one or more additional agents.Examples of additional agents include anti-TNF treatments (for examplemonoclonal antibody such as infliximab (Remicade), adalimumab (Humira),certolizumab pegol (Cimzia), and golimumab (Simponi), or a circulatingreceptor fusion protein such as etanercept (Enbrel)), antimetabolite andantifolate drug (for example Methotrexate), or targeted kinaseinhibitors (for example JAK family inhibitors Ruxolitinib, Tofacitinib,CYT387, Lestaurtinib, Pacritinib and TG101348).

Another embodiment of this invention provides a method of treatingTrypanosoma cruzi infection in a mammal, comprising administering tosaid mammal in need thereof one or more compounds of Formula I or apharmaceutically acceptable salt thereof in an amount effective to treatsaid Trypanosoma cruzi infection.

Another embodiment of this invention provides a method of treatingSjogren's syndrome in a mammal, comprising administering to said mammalin need thereof one or more compounds of Formula I or a pharmaceuticallyacceptable salt thereof in an amount effective to treat said syndrome.

Another embodiment of this invention provides a method of treatingendometriosis in a mammal, comprising administering to said mammal inneed thereof one or more compounds of Formula I or a pharmaceuticallyacceptable salt thereof in an amount effective to treat saidendometriosis.

Another embodiment of this invention provides a method of treatingdiabetic peripheral neuropathy in a mammal, comprising administering tosaid mammal in need thereof one or more compounds of Formula I or apharmaceutically acceptable salt thereof in an amount effective to treatsaid diabetic peripheral neuropathy.

Another embodiment of this invention provides a method of treatingprostatitis in a mammal, comprising administering to said mammal in needthereof one or more compounds of Formula I or a pharmaceuticallyacceptable salt thereof in an amount effective to treat saidprostatitis.

Another embodiment of this invention provides a method of treatingpelvic pain syndrome in a mammal, comprising administering to saidmammal in need thereof one or more compounds of Formula I or apharmaceutically acceptable salt thereof in an amount effective to treatsaid pelvic pain syndrome.

Another embodiment of this invention provides a method of treating aneurodegenerative disease in a mammal, comprising administering to saidmammal in need thereof one or more compounds of Formula I or apharmaceutically acceptable salt thereof in an amount effective to treatsaid neurodegenerative disease.

As used herein, an “effective amount” means an amount of compound that,when administered to a mammal in need of such treatment, is sufficientto (i) treat a particular disease, condition, or disorder which can betreated with a compound of Formula I, or (ii) attenuate, ameliorate, oreliminate one or more symptoms of the particular disease, condition, ordisorder described herein.

The amount of a compound of Formula I that will correspond to such anamount will vary depending upon factors such as the particular compound,disease condition and its severity, the identity (e.g., weight) of themammal in need of treatment, but can nevertheless be routinelydetermined by one skilled in the art.

As used herein, the term “mammal” refers to a warm-blooded animal thathas or is at risk of developing a disease described herein and includes,but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters,and primates, including humans.

The compounds of the present invention can be used in combination withone or more additional therapeutic agents that work by the same or adifferent mechanism of action. Examples of additional therapeutic agentsinclude anti-inflammatory compounds, steroids (e.g., dexamethasone,cortisone and fluticasone), analgesics such as NSAIDs (e.g., aspirin,ibuprofen, indomethacin, and ketoprofen), and opioids (such asmorphine), and chemotherapeutic agents.

Also provided herein is a pharmaceutical combination comprising aneffective amount of: (a) at least one compound of Formula I; and (b) atleast one additional therapeutic agent selected from anti-inflammatorycompounds, steroids (e.g., dexamethasone, cortisone and fluticasone),analgesics such as NSAIDs (e.g., aspirin, ibuprofen, indomethacin, andketoprofen), and opioids (such as morphine), for use in the treatment ofpain in a mammal, wherein (a) and (b) can be in separate dosage forms orin the same dosage form.

The term “pharmaceutical combination” as used herein refers to apharmaceutical therapy resulting from the mixing or combining of morethan one active ingredient and includes both fixed and non-fixedcombinations of the active ingredients. The term “fixed combination”means that at least one of the compounds of Formula I, and at least oneadditional therapeutic agent are both administered to a patientsimultaneously in the form of a single entity or dosage. The term“non-fixed combination” means that at least one of the compounds ofFormula I, and at least one additional therapeutic agent, areadministered to a patient as separate entities either simultaneously orsequentially with variable intervening time limits, wherein suchadministration provides effective levels of the two or more compounds inthe body of the patient. These also apply to cocktail therapies, e.g.the administration of three or more active ingredients.

Also provided herein is a method of treating pain in a mammal,comprising co-administering to a mammal in need thereof an effectiveamount of: (a) at least one compound of Formula I; and (b) at least oneadditional therapeutic agent selected from anti-inflammatory compounds,steroids (e.g., dexamethasone, cortisone and fluticasone), analgesicssuch as NSAIDs (e.g., aspirin, ibuprofen, indomethacin, and ketoprofen),opioids (such as morphine), calcitonin gene-related peptide receptorantagonists, subtype-selective ion channel modulators, anticonvulsants(for example Pregabalin and gabapentin), dual serotonin-norepinephrinreuptake inhibitors (for example duloxetine, venlafaxine andmilnacipran), and tricyclic antidepressants (such as amitriptyline,nortriptyline and desipramine).

Another embodiment of this invention provides a method of treatingdiseases related to an imbalance of the regulation of bone remodeling ina mammal, comprising administering to said mammal in need thereof one ormore compounds of Formula I or a pharmaceutically acceptable saltthereof in an amount effective to treat said disease. In one embodiment,the disease is osteoporosis, rheumatoid arthritis, and bone metastases.

In one embodiment, the method for treating diseases related to animbalance of the regulation of bone remodeling in a mammal comprisesadministering a TrkA inhibitor of the invention in combination with oneor more additional therapeutic agents or therapies. Examples ofadditional therapeutic agents or therapies include anti-TNF treatments(for example monoclonal antibody such as infliximab (Remicade),adalimumab (Humira), certolizumab pegol (Cimzia), and golimumab(Simponi), or with a circulating receptor fusion protein such asetanercept (Enbrel)), antimetabolite and antifolate drug (for exampleMethotrexate), or targeted kinase inhibitors (for example JAK familyinhibitors Ruxolitinib, Tofacitinib, CYT387, Lestaurtinib, Pacritiniband TG101348).

The term “co-administering” is meant to encompass administration of theselected therapeutic agents to a single patient, and is intended toinclude treatment regimens in which the agents are administered by thesame or different route of administration or at the same or differenttimes. This term encompasses administration of two or more agents to amammal so that both agents and/or their metabolites are present in themammal at the same time. It includes simultaneous administration inseparate compositions, administration at different times in separatecompositions, and/or administration in a composition in which bothagents are present. In some embodiments, the compound(s) of theinvention and the other therapeutic agent(s) are administered in asingle composition. In some embodiments, compound(s) of the inventionand the other agent(s) are admixed in the composition.

Also provided herein is a medicament containing a compound of Formula Ifor treatment of pain in a mammal in combination with an additionaltherapeutic agent selected from anti-inflammatory compounds, steroids(e.g., dexamethasone, cortisone and fluticasone), analgesics such asNSAIDs (e.g., aspirin, ibuprofen, indomethacin, and ketoprofen), andopioids (such as morphine).

Also provided herein is a medicament containing a therapeutic agentselected from anti-inflammatory compounds, steroids (e.g.,dexamethasone, cortisone and fluticasone), analgesics such as NSAIDs(e.g., aspirin, ibuprofen, indomethacin, and ketoprofen), and opioids(such as morphine) for treatment of pain in a mammal in combination witha compound of Formula I.

Compounds of the invention may be administered by any convenient route,e.g. into the gastrointestinal tract (e.g. rectally or orally), thenose, lungs, musculature or vasculature, or transdermally or dermally.Compounds may be administered in any convenient administrative form,e.g. tablets, powders, capsules, solutions, dispersions, suspensions,syrups, sprays, suppositories, gels, emulsions, patches etc. Suchcompositions may contain components conventional in pharmaceuticalpreparations, e.g. diluents, carriers, pH modifiers, sweeteners, bulkingagents, and further active agents. If parenteral administration isdesired, the compositions will be sterile and in a solution orsuspension form suitable for injection or infusion. Such compositionsform a further aspect of the invention.

Another formulation may be prepared by mixing a compound describedherein and a carrier or excipient. Suitable carriers and excipients arewell known to those skilled in the art and are described in detail in,e.g., Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms andDrug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins,2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice ofPharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe,Raymond C. Handbook of Pharmaceutical Excipients. Chicago,Pharmaceutical Press, 2005. The formulations may also include one ormore buffers, stabilizing agents, surfactants, wetting agents,lubricating agents, emulsifiers, suspending agents, preservatives,antioxidants, opaquing agents, glidants, processing aids, colorants,sweeteners, perfuming agents, flavoring agents, diluents and other knownadditives to provide an elegant presentation of the drug (i.e., acompound described herein or pharmaceutical composition thereof) or aidin the manufacturing of the pharmaceutical product (i.e., medicament).

Accordingly, another aspect of the present invention provides apharmaceutical composition, which comprises a compound of Formula I or apharmaceutically acceptable salt thereof, as defined hereinabove,together with a pharmaceutically acceptable diluent or carrier.

According to another embodiment, the present invention provides acompound of Formula I or a pharmaceutically acceptable salt thereof, foruse in the treatment of pain in a mammal. In one embodiment, the pain ischronic pain. In one embodiment the pain is acute pain. In oneembodiment, the pain is inflammatory pain, neuropathic pain, or painassociated with cancer, surgery, or bone fracture.

According to another embodiment, the present invention provides acompound of Formula I or a pharmaceutically acceptable salt thereof, foruse in the treatment of cancer in a mammal.

In another embodiment, the present invention provides a compound ofFormula I or a pharmaceutically acceptable salt thereof, for use in thetreatment of inflammation or an inflammatory disease or disorder in amammal. In one embodiment, the inflammatory disease is inflammatory lungdiseases (such as asthma), interstitial cystitis, bladder pain syndrome,inflammatory bowel diseases (including ulcerative colitis and Crohn'sdisease), and inflammatory skin diseases such as atopic dermatitis.

In another embodiment, the present invention provides a compound ofFormula I or a pharmaceutically acceptable salt thereof, for use in thetreatment of infectious diseases, for example Trypanosoma cruziinfection, in a mammal.

In another embodiment, the present invention provides a compound ofFormula I or a pharmaceutically acceptable salt thereof, for use in thetreatment of Sjogren's syndrome in a mammal.

In another embodiment, the present invention provides a compound ofFormula I or a pharmaceutically acceptable salt thereof, for use in thetreatment of endometriosis in a mammal.

In another embodiment, the present invention provides a compound ofFormula I or a pharmaceutically acceptable salt thereof, for use in thetreatment of diabetic peripheral neuropathy in a mammal.

In another embodiment, the present invention provides a compound ofFormula I or a pharmaceutically acceptable salt thereof, for use in thetreatment of prostatitis in a mammal.

In another embodiment, the present invention provides a compound ofFormula I or a pharmaceutically acceptable salt thereof, for use in thetreatment of pelvic pain syndrome in a mammal.

In another embodiment, the present invention provides a compound ofFormula I or a pharmaceutically acceptable salt thereof, for use in thetreatment of a neurodegenerative disease in a mammal.

According to a further aspect, the present invention provides the use ofa compound of Formula I or a pharmaceutically acceptable salt thereof,in the manufacture of a medicament for the treatment of a conditionselected from pain, cancer, inflammation, neurodegenerative disease orTrypanosoma cruzi infection. In one embodiment, the condition is chronicpain. In one embodiment, the condition is acute pain. In one embodiment,the pain is inflammatory pain, neuropathic pain, or pain associated withcancer, surgery, or bone fracture. In one embodiment, the condition iscancer. In one embodiment, the condition is inflammation. In oneembodiment, the condition is a neurodegenerative disease. In oneembodiment, the condition is Trypanosoma cruzi infection. In oneembodiment, the condition is Sjogren's syndrome. In one embodiment, thecondition is endometriosis. In one embodiment, the condition is diabeticperipheral neuropathy. In one embodiment, the condition is prostatitis.In one embodiment, the condition is pelvic pain syndrome.

EXAMPLES

The following examples illustrate the invention. In the examplesdescribed below, unless otherwise indicated all temperatures are setforth in degrees Celsius. Reagents were purchased from commercialsuppliers such as Aldrich Chemical Company, Lancaster, TCI or Maybridge,and were used without further purification unless otherwise indicated.THF, DCM, toluene, DMF and dioxane were purchased from Aldrich inSure/Seal™ bottles and used as received.

The reactions set forth below were done generally under a positivepressure of nitrogen or argon or with a drying tube (unless otherwisestated) in anhydrous solvents, and the reaction flasks were typicallyfitted with rubber septa for the introduction of substrates and reagentsvia syringe. Glassware was oven dried and/or heat dried.

Column chromatography was done on a Biotage system (Manufacturer: DyaxCorporation) having a silica gel or C-18 reverse phase column, or on asilica SepPak cartridge (Waters).

BIOLOGICAL ASSAYS Example A-1 TrkA Kinase Binding Assay

TrkA binding activity was determined in a TrkA LanthaScreen™ Eu KinaseBinding Assay. 5 nM His-tagged recombinant human TrkA (6HIS taggedcytoplasmic domain from Invitrogen, Catalog No. PV3144) was incubatedwith 4 nM Alexa-Fluor® Tracer 236 (Invitrogen Cat. No. PV5592), 2 nMbiotinylated anti-His (Invitrogen Cat. No. PV6090), and 2 nMeuropium-labeled Streptavidin (Invitrogen Cat. No. PV5899), in buffer(25 mM MOPS, pH 7.5, 5 mM MgCl₂, 0.005% Triton X-100). Three fold serialdilutions of compounds of the invention in DMSO were added to a finalpercentage of 2% DMSO. After 60-minute incubation at 22° C., thereaction was measured using the EnVision mutlimode plate reader(PerkinElmer) via TR-FRET dual wavelength detection at 615 nM and 665nM. The percent of control was calculated using a ratiometric emissionfactor. The IC₅₀ values were determined by fitting a four parametermodel to the percent of control data.

Table A provides averaged IC₅₀ values for compounds of the inventionwhen tested in the assay of Example A, where A represents an averagedIC₅₀ value <100 nM; B represents an averaged IC₅₀ value from 100 to1,000 nM, and C represents an averaged IC₅₀ value between >1,000 nM and3,000 nM.

TABLE A TrkA Enzyme IC₅₀ Ex. # (nM)  1 A  2 A  3 A  4 B  5 B  6 A  7 B 8 B  9 B  10 A  11 A  12 A  13 B  14 B  15 A  16 A  17 B  18 B  19 B 20 B  21 B  22 B  23 B  24 B  25 A  26 A  27 A  28 A  29 A  30 A  31 A 32 A  33 A  34 A  35A A  35B B  36 B  37 B  38 B  39 A  40 B  41 A  42A  43 B  44 A  45 A  46 A  47 B  48 B  49 B  50 B  51 B  52 B  53 B  54B  55 A  56 A  57 A  58 A  59 A  60 A  61 A  62 A  63 A  64 A  65 A  66A  67 A  68 A  69 A  70 A  71 A  72 A  73 A  74 A  75 A  76 A  77 A  78A  79 A  80 A  81 A  82 A  83 A  84 A  85 A  86 A  87 A  88 A  89 A  90A  91 A  92 A  93 A  94 A  95 A  96 A  97 A  98 C  99 A 100 A 101 A 102A 103 A 104 A 105 A 106 A 107 A 108 A 109 A 110 A 111 A 112 A 113 B 114A 115 A 116 A 117 A 118 A 119 A 120 A 121 A 122 A 123 A 124 A 125 A 126B 127 B 128 B 129 A 130 A 131 A 132 A 133 A 134 A 135 C 136 A 137 A 138B 139 A 140 A 141 A 142 A 143 A 144 A 145 B 146 A 147 A 148 A 149 A 150A 151 A 152 A 153 A 154 A 155 A 156 A 157 A 158 A 159 A 160 A

p38α Kinase Binding Assay

p38α binding activity was determined in a p38α LanthaScreen™ Eu KinaseBinding Assay. 5 nM of inactive, GST-tagged recombinant human p38α(GST-tagged cytoplasmic domain from Invitrogen, Catalog No. PV3305) wasincubated with 5 nM Alexa-Fluor® Tracer 199 (Invitrogen Cat. No.PV5830), and 2 nM europium labeled anti-GST antibody (Invitrogen Cat.No. PV5594), in buffer (25 mM [Na⁺] HEPES pH 7.3, 10 mM MgCl₂, 100 μMNaVO₄). Three fold serial dilutions of compounds of the invention inDMSO were added to a final percentage of 2% DMSO. After 60-minuteincubation at 22° C., the reaction was measured using the EnVisionmultimode plate reader (PerkinElmer) via TR-FRET dual wavelengthdetection at 615 nM and 665 nM. The percent of control was calculatedusing a ratiometric emission factor. The IC₅₀ values were determined byfitting a four parameter model to the percent of control data. Thecompounds of Examples 1-160 were tested in this assay, and all compoundswere found to be about 1000 fold more potent against TrkA than p38α.

Example B Off-Target Kinase Profiling

Representative compounds (Examples 12, 32, 26 and 2) of the inventionwere tested for off-target kinase activity at a concentration of 10μM byMillipore, Inc. in their KinaseProfiler™ service against all the kinasesavailable in their full kinase panel. Compounds were run in duplicate ata concentration of ATP near the Km for each individual kinase accordingto Millipore's specifications. The results are shown in Table B. Dataare reported as percent of control (POC) and are the average of the tworeplicates.

In the KinaseProfiler™ the representative compounds showed remarkableand unexpected selectivity for inhibiting TrkA and TrkB versus otherkinases in the panel. In fact, the compounds were largely inactiveagainst off-target kinases at a concentration of 10 μM, and thus wouldnot be expected to inhibit off-target kinases at therapeutic doses inmammals. The ability of compounds of the invention to selectivelyinhibit the Trk pathway without inhibiting other off-target kinasescould translate into drug profiles that are essentially free ofside-effects related to inhibition of off-target kinases. Such a drugprofile would represent a safer approach to treating pain, inflammation,cancer and certain skin diseases than has been previously reported.

TABLE B Example 12 Example 32 Example 26 Example 2 Kinase Avg. POC Avg.POC Avg. POC Avg. POC Abl2 118 121.5 105 112.5 Abl-P 135.5 124.5 131146.5 AKT1 105.5 92 100 130.5 AKT2 127 121 130 132 AKT3 94 77.5 96 116.5ALK 103 127 117 111 ALK4 101 100.5 102.5 98.5 AMPK 117 138.5 122.5 152.5(A1/B1/G1) ARK5 99.5 118.5 100.5 109.5 AURKA 111 112.5 107.5 126 Axl 106119.5 107 113.5 BLK_m 112 111 103.5 126 Bmx 115.5 106.5 109.5 113 BrSK1111.5 114.5 105.5 119 BrSK2 147 128.5 118 139.5 BTK 127 119 139 111.5CAMK1 102 100 106 109.5 CAMK1d 137 114 97 127 CAMK2b 106 102.5 107 106.5CAMK2d 110.5 108.5 99.5 119 CAMK2g 107.5 105 101 107.5 CAMK4 113.5 102121 137.5 CDK1/cyclinB 107.5 104 103 122.5 CDK2/cyclinA 112 118 114.5127 CDK2/cyclinE 96.5 106 97.5 116.5 CDK3/cyclinE 98.5 102.5 101.5 105.5CDK5/p25 104 106 109 107.5 CDK5/p35 106.5 112 110.5 124 CDK6/cyclinD3103 108 104.5 100 CDK7/cyclinH/ 101 122.5 113.5 111 MAT1 CDK9/cyclinT1106 106.5 112.5 127 CHK1 99.5 103 70.5 106.5 CHK2 92 112 109 119 CK1_y101 107.5 104.5 100.5 CK1delta 109.5 135.5 121.5 117.5 CK1gamma1 98.5111.5 106.5 116.5 CK1gamma2 114.5 101.5 112.5 142.5 CK1gamma3 104.5 102102.5 118 CK2 98 97 110.5 107 CK2alpha2 107.5 104 114 125 CLK2 100 105.5108.5 115.5 CLK3 100 109 106 108 c-RAF 96 101.5 106.5 103.5 CSK 131.5123 118.5 124 DAPK1 136 131 135 108.5 DAPK2 102.5 103 108.5 123.5 DAPK3103 111 103 125.5 DCAMKL2 169 146 135 157.5 DDR2 107 116 111 113 DMPK104 98.5 106 105 DRAK1 114 105.5 125 108.5 DYRK2 97.5 97.5 103 98 eEF-2K140 115 127.5 138 EGFR 109.5 102 108 114 EphA1 100 114 101 85 EphA2 113118 102 129 EphA3 114.5 122 128 123.5 EphA4 114.5 103 110 111.5 EphA5118.5 104.5 106.5 119 EphA7 96.5 100.5 108 116 EphA8 122.5 109 118.5128.5 EphB1 114 145.5 116.5 108.5 EphB2 112 96.5 109.5 125 EphB3 89 87.597 110 EphB4 121 106 115 118.5 ErbB4 122 108.5 115.5 148 ERK1 105 107109.5 120.5 ERK2 106.5 128.5 107.5 112.5 FAX 104 116.5 105 116.5 FAK2111 101.5 104.5 120 Fer 100.5 85 98 110.5 Fes 110 112.5 100.5 129.5FGFR1 90 104.5 104.5 114 FGFR2 114 110.5 112 112.5 FGFR3 109 107 101113.5 FGFR4 119 139.5 123 124 Fgr 114.5 109.5 114.5 131 Flt1 93 103 104105.5 Flt3 90 115 97.5 96.5 Flt4 83.5 98 106 99 Fms 91 102 96 82 Fyn92.5 111 115.5 123.5 GRK5 83.5 90 86 106.5 GRK6 103 101 100.5 103.5 GRK7117 117.5 118 108.5 GSK3alpha 119.5 112.5 115.5 123.5 GSK3beta 109.584.5 124.5 126 Haspin 97 94 92 92.5 Hck 103.5 98 91.5 85.5 HIPK1 102.5115 111 97 HIPK2 91.5 99.5 103 97 HIPK3 102.5 107 111 119.5 IGF-1R 8084.5 60.5 18 IGF-1R Activated 102.5 112.5 98 95 IKKalpha 119.5 102 112.5141.5 IKKbeta 102 105.5 103.5 116 IR 92 109 82.5 44 IR Activated 109111.5 106 103 IRAK1 102.5 113.5 110.5 107 IRAK4 95.5 99 102 125.5 IRR 91109.5 89 2.5 ITK 114.5 124 122 117.5 JAK2 122.5 122.5 134.5 233 JAK3 112109.5 112 142.5 JNK1alpha1 109.5 118 112 94 JNK2alpha2 96 102.5 104103.5 JNK3 107.5 104 116 117.5 KDR 119.5 129 144.5 123.5 KIT 102.5 94.594 104 Lck 92 104.5 96.5 97.5 LIMK1 97.5 95 102 105 LKB1 91 100 95 103.5LOK 116 103.5 109 109.5 Lyn 104.5 106.5 110.5 115 MAP3K5 111 116 116.5105 MAP4K2 107.5 119.5 121 110 MAPKAP-K2 122.5 117.5 120 137.5 MAPKAP-K3112 105 108.5 128 MAPKAP-K5 96 108 101.5 113.5 MARK1 104 98.5 98.5 103MARK2 105.5 107.5 102.5 109 MEK1 106.5 102 97 100.5 MELK 67 98 86 142Mer 98 104 98 109.5 Met 109 118.5 81 148.5 MINK 102 124 126.5 110.5MKK4_m 144.5 133 99.5 102.5 MKK6 123 134.5 121.5 130 MKK7beta 122.5138.5 144.5 129.5 MKNK2 103.5 99.5 99.5 106.5 MLK1 103.5 104.5 105.5 75MRCKalpha 139 131 124.5 127.5 MRCKbeta 103.5 103 110 129.5 MSK1 127.5118 114 113.5 MSK2 127 99.5 107.5 112 MSSK1 112.5 105.5 120.5 116 MST192 105.5 102 111.5 MST2 106.5 111.5 111 110.5 MST3 131.5 130.5 108.5 120mTOR 104.5 94.5 102.5 116 mTOR/FKBP12 105.5 113.5 107.5 105 MuSK 98.5104.5 99.5 103.5 MYLK 99 97.5 101 100 NEK11 84.5 108 113.5 108.5 NEK291.5 108 100.5 104 NEK3 102 113 105 105 NEK6 121 123 123.5 125.5 NEK7133.5 122.5 126 94.5 NLK 115.5 125.5 100.5 111 p38alpha 110 96.5 104.5102.5 p38beta 115.5 119 115.5 113 p38delta 99.5 113.5 102 96.5 p38gamma111 116.5 118 115 p70S6K 124.5 110.5 116 172 PAK2 97 108.5 99.5 104 PAK4103 98 100.5 95 PAK5 143 111 121.5 109.5 PAK6 139 116.5 116.5 119.5 PASK125.5 137 124.5 143 PDGFRalpha 104.5 112.5 104.5 123 PDGFRbeta 125.5131.5 122.5 149 PDK1 105.5 101.5 115 120.5 PhKgamma2 110 102.5 108.5 113Pim-1 106 109 97.5 173 Pim-2 118.5 116.5 120.5 148 Pim-3 100.5 112 98 98PKAC-alpha 120.5 90 116 138.5 PKCalpha 104 110 107.5 96 PKCbetaI 93.5 8089 99 PKCbetaII 100 100.5 99 95.5 PKCdelta 97.5 99 105 95 PKCepsilon97.5 97.5 106.5 101.5 PKCeta 100 111.5 98 107 PKCgamma 104.5 104 99 102PKCiota 69.5 71 85.5 95.5 PKCtheta 117.5 117 109 101 PKCzeta 99.5 115108.5 122.5 PKD1 115 98.5 113.5 110.5 PKD2 94 110.5 102 102 Plk1 98.5108 108 95 Plk2 103.5 103 101.5 102 Plk3 115 103.5 119 103 PRK2 97.599.5 110.5 128 PRKG1alpha 89.5 84 98 127.5 PRKG1beta 95.5 80.5 111.5 122PrKX 118.5 110 109 152 PTK5 100 104 110 122 PTK6 125.5 100 121 129 Ret85 100.5 106.5 118.5 RIPK2 99 99.5 98 108 ROCK-I 116.5 103 112 116.5ROCK-II 99 106 110 108 Ron 116.5 107 101 106.5 Ros 97.5 97.5 106.5 106.5Rse 106 105 109.5 109 Rsk1 107.5 111.5 121 117 Rsk2 103 92.5 105.5 137Rsk3 90 92 76.5 106 Rsk4 101 95 99.5 140 SGK1 129 119 97.5 150 SGK2 148123.5 123.5 166.5 SGK3 143.5 134 104 137.5 SIK 133.5 97 121.5 121.5 SRC97 108.5 104.5 99.5 SRPK1 97.5 99.5 102.5 122 SRPK2 101.5 106.5 106 106STK33 106.5 115 111 110.5 Syk 108.5 115 93.5 115 TAK1 97 99.5 108.5 106TAO1 104 100 105.5 110.5 TAO2 121 104 111 110 TAO3 99 105 109 111 TBK1103 108.5 113 116 TEC Activated 122.5 108.5 113.5 153 Tie2 104.5 121106.5 126 TLK2 98 92 97 100 TNK2 117.5 132 123 100.5 TrkA −0.5 0 0.5 1.5TrkB 1 −0.5 1.5 −2 TSSK1 79 88.5 71.5 106 TSSK2 139 120.5 128 118.5 Txk139 127 119 125 ULK2 99 103 102 99 ULK3 89.5 92 92.5 105 VRK2 95 100.598 109 WNK2 106.5 108.5 108 99 WNK3 112.5 103.5 103.5 109.5 Yes 119.5114.5 117.5 132.5 ZAP-70 140 124 120.5 124

PREPARATION OF SYNTHETIC INTERMEDIATES Intermediate 1

Preparation of phenyl (3-methyl-1-phenyl-1H-pyrazol-5-yl)carbamate

To a solution of 3-methyl-1-phenyl-1H-pyrazol-5-amine (500 mg, 2.887mmol) in EtOAc (25 mL) was added aqueous sodium hydroxide (2 M) (4.33mL, 8.660 mmol) followed by phenyl carbonochloridate (0.54 mL, 4.33mmol). The reaction was stirred at ambient temperature overnight,diluted with EtOAc (10 mL) and the phases were separated. The organicphase was washed with H₂O (10 mL), brine (10 mL), dried (MgSO₄),filtered and concentrated to a pale yellow solid. The crude product wastriturated with hexanes (20 mL) and filtered, yielding pure product asoff-white solid. MS (apci) m/z=294.1 (M+H).

Intermediate 2

3-methoxy-4-methyl-1-phenyl-1H-pyrazol-5-amine Step A: Preparation of5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one

A mixture of ethyl 2-cyanopropanoate (5.0 g, 46 mmol) andphenylhydrazine (5.9 g, 46 mmol) in dioxane (10 mL) was heated at 110°C. for 17 hours. The mixture was cooled to ambient temperature andconcentrated. The residual solid was triturated with cold EtOH andsuspended in Et₂O. The solid was filtered, washed with Et₂O and driedunder vacuum to give the product as a white solid (3.4 g, 39% yield). MS(apci) m/z=190.0 (M−H).

Step B: Preparation of 3-methoxy-4-methyl-1-phenyl-1H-pyrazol-5-amine

To a fine suspension of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one(300 mg, 1.59 mmol) in 1:1 CH₂Cl₂-MeOH (6.0 mL) was added 2M TMSCHN₂ inhexanes (951 μL, 1.90 mmol). The mixture was stirred at ambienttemperature for 2 hours and additional 2M TMSCHN₂ in hexanes (1.0 mL)was added. The mixture was stirred for 2 hours and concentrated. Theresidual syrup was partitioned into H₂O and 50% EtOAc-hexanes andstirred for 15 minutes. The organic layer was removed and the aqueouslayer was extracted with 50% EtOAc-hexanes (2×). The combined organicfractions were washed with saturated NaCl and dried over MgSO₄/activatedcarbon. The dried solution was eluted through a SiO₂ plug eluting with50% EtOAc-hexanes. The eluent was concentrated to a colorless syrup thatwas dried under vacuum to afford the title compound as a white solid(153 mg, 47% yield). ¹H NMR (CDCl₃) δ 7.52 (d, J=7.7 Hz, 2H), 7.42 (t,J=7.6 Hz, 2H), 7.24 (t, J=7.3 Hz, 1H), 3.94 (s, 3H), 3.59 (br s, 2H),1.83 (s, 3H) ppm.

Intermediate 3

phenyl (3-methoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)carbamate

A solution of 3-methoxy-4-methyl-1-phenyl-1H-pyrazol-5-amine (140 mg,0.689 mmol) in EtOAc (3.0 mL) was cooled to 0° C. and 2M NaOH (689 μL,1.38 mmol) and phenylchloroformate (129 μL, 1.03 mmol) were addedsequentially. The mixture was stirred for 5 minutes, allowed to reachambient temperature and stirred for 3 hours. The reaction mixture wasdiluted with hexanes (3 mL) and washed with H₂O (2×), 1M HCl, H₂O andsaturated NaCl. The organic fraction was dried over MgSO₄/activatedcarbon and filtered through a SiO₂ plug eluting with 50% EtOAc-hexanes.The eluent was concentrated, and the residual colorless syrup wasdissolved in dry Et₂O and concentrated to a white foam. The foam wassonicated under hexanes until a fine granular suspension formed. Thesolvent was decanted, the residual solid was washed with hexanes anddried under vacuum to afford the title compound as a white solid (185mg, 83% yield). ¹H NMR (CDCl₃) δ 7.50-7.10 (m, 9H), 6.75 (br unresolved,1H), 6.47 (s, 1H), 3.97 (s, 3H), 1.96 (s, 3H) ppm.

Intermediate 4

3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-amine Step A: Preparation of5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one

A mixture of ethyl 2-cyanopropanoate (5.0 g, 46 mmol) andphenylhydrazine (5.9 g, 46 mmol) in dioxane (10 mL) was heated at 110°C. for 17 hours. The crude material was cooled to ambient temperature,concentrated, and triturated with cold EtOH and Et₂O. The resultantsolid was filtered, washed with Et₂O, and dried under vacuum to give theproduct as a white solid (3.4 g, 39% yield). MS (apci) m/z=190.0 (M−H).

Step B: Preparation of 3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-amine

To a suspension of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one (10.0g, 52.9 mmol) in DMF (100 mL) was added K₂CO₃ (14.6 g, 106 mmol) andbromoethane (4.34 mL, 58.1) at ambient temperature. After stirring for17 hours, the reaction mixture was treated with EtOAc and washed withwater (3×) and brine, dried (MgSO₄), filtered, and concentrated to givethe product (5.35 g, 47% yield). MS (apci) m/z=218.1 (M+H).

Intermediate 5

phenyl 3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate

Prepared by the method as described for Intermediate 1 using3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-amine instead of3-methyl-1-phenyl-1H-pyrazol-5-amine. The material (4.43 g, 13.13 mmol,99.8% yield) was used without purification. MS (apci) m/z=338.1 (M+H).

Intermediate 6

3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-amine

To a stirred solution of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one(1.00 g, 5.29 mmol) in MeCN (20 mL) was added POBr₃ (2.27 g, 7.93 mmol).The reaction mixture was heated at reflux for 3 hours. The reaction wasconcentrated under vacuum. The residue was taken up in DCM. Saturatedaqueous NaHCO₃ solution was carefully added. The aqueous layer wasextracted with DCM. The combined organic extracts were washed withbrine, dried and concentrated. The residue was purified by flashchromatography on silica gel (1:2 hexane/EtOAc to give the titlecompound (0.23 g, 17% yield). MS (apci) m/z=252.0; 254.0 (M+H).

Intermediate 7

5-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-1-methylpyridin-2(1H)-one

3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-amine (763 mg, 3.03 mmol),1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)one (1.42 g, 6.05 mmol), K₂CO₃ (1.67 g, 12.1 mmol) and Pd(PPh₃)₄(350 mg,0.30 mmol) were combined in toluene (10 mL), water (5 mL) and EtOH (2.5mL) and warmed to 95° C. in a sealed tube for 16 hours. The cooledmixture was filtered and the filtrate partitioned between water (30 mL)and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (2×20 mL)and the combined organic extracts were washed with brine (20 mL), driedover Na₂SO₄, filtered and concentrated under vacuum. The residue waspurified by silica column chromatography eluting with 2% MeOH/DCM toafford the title compound (504 mg, 59% yield) as a yellow foam. MS(apci) m/z=281.2 (M+H).

Intermediate 8

phenyl(4-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)carbamate

To a suspension of5-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-1-methylpyridin-2(1H)-one(2.80 g, 9.99 mmol) in EtOAc (120 mL) was added 2N NaOH (14.98 mL, 29.97mmol) followed by phenyl chloroformate (2.5 mL, 19.98 mmol). The mixturewas stirred at ambient temperature for 16 hours then partitioned betweenwater (100 mL) and EtOAc (100 mL) and the aqueous layer extracted withEtOAc (2×50 mL). The combined organic extracts were washed withsaturated NaHCO₃ (50 mL) and brine (50 mL) then dried over Na₂SO₄,filtered and concentrated to afford the title compound as a pale yellowsyrup which was used directly without purification, assuming 100% yield.MS (apci) m/z=401.2 (M+H).

Intermediate 9

Preparation of1-methyl-4-(4-methyl-5-(phenoxycarbonylamino)-1-phenyl-1H-pyrazol-3-yl)-3-(phenoxycarbonyl)-1H-imidazol-3-iumchloride Step A: Preparation of2-methyl-3-(1-methyl-1H-imidazol-4-yl)-3-oxopropanenitrile

Propiononitrile (0.893 g, 16.2 mmol) was added dropwise to a 1M solutionof LHMDS (13.0 mL, 13.0 mmol) in THF at −78° C. The mixture was stirredfor 30 minutes and a solution of ethyl1-methyl-1H-imidazole-4-carboxylate (1.00 g, 6.49 mmol) in THF (20 mL,heated to dissolve the starting material) was added dropwise. Thereaction was allowed to warm to ambient temperature, stirred overnight,poured into ice water (50 mL) and extracted with EtOAc (100 mL). The pHwas adjusted to 6.5 using 2N HCl and the mixture was extracted withEtOAc (100 mL). The pH was then adjusted to 6 using 2N HCl and themixture was extracted with EtOAc (2×100 mL). The combined extracts fromthe pH 6.5 and pH 6 extractions were dried (MgSO₄), filtered andconcentrated to provide the title compound (1.02 g, 6.25 mmol, 96.4%yield). MS (apci) m/z=164.2 (M+H).

Step B: Preparation of4-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-phenyl-1H-pyrazol-5-aminehydrochloride

A pressure vessel was charged with2-methyl-3-(1-methyl-1H-imidazol-4-yl)-3-oxopropanenitrile (1.00 g, 6.13mmol), absolute EtOH (12.3 mL, 6.13 mmol) and phenylhydrazinehydrochloride (0.975 g, 6.74 mmol). The reaction was sealed, heated at80° C. overnight and concentrated to afford the title compound (1.70 g,5.87 mmol, 95.7% yield). MS (apci) m/z=254.1 (M+H).

Step C: Preparation of1-methyl-4-(4-methyl-5-(phenoxycarbonylamino)-1-phenyl-1H-pyrazol-3-yl)-3-(phenoxycarbonyl)-1H-imidazol-3-iumchloride

4-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-phenyl-1H-pyrazol-5-aminehydrochloride (2 g, 6.90 mmol) was dissolved in 100 mL of CHCl₃ andpyridine (6.386 mL, 78.96 mmol) was added followed byphenylchloroformate (2.972 mL, 23.69 mmol). The reaction was stirred atambient for 2 hours and quenched with 1N NaOH (100 mL). The layers wereseparated and the aqueous layer was washed with DCM. The combinedorganic extracts were dried (MgSO₄) and concentrated. The crude materialwas purified by silica gel column chromatography, eluting with 25-100%acetone/hexanes, to afford the title compound (2.35 g, 4.752 mmol, 68.8%yield). MS (apci) m/z=494.1 (M+H). This intermediate needs to be reactedwith two equivalents of an amine to afford the desired urea products.

Intermediate 10

5-amino-N,4-dimethyl-l-phenyl-1H-pyrazole-3-carboxamide Step A:Preparation of ethyl 3-cyano-2-oxobutanoate

To a solution of lithium bis(trimethylsilyl)amide (1M in THF, 46.4 mL,46.39 mmol) in THF (100 mL) under N₂ at −78° C. was addedpropiononitrile (3.08 mL, 53.01 mmol) dropwise over 2 min. The mixturewas stirred at −78° C. for 1 hour, then diethyl oxalate (6.0 mL, 44.18mmol) was added dropwise over 5 minutes. The reaction mixture wasstirred at −78° C. for 45 minutes, then at 0° C. for 4 hours, then wasdiluted with H₂O (100 mL) and extracted with Et₂O (100 mL). The aqueousphase was neutralized with 6M HCl (7 mL), then extracted with Et₂O(3×100 mL), and the combined organic extracts were washed with brine(100 mL), dried (MgSO₄), filtered, and concentrated to afford theproduct as a yellow syrup (6.6 g, 96% yield). ¹H NMR (CDCl₃) δ 4.46 (q,2H), 4.38 (dq, 1H), 1.44 (t, 3H), 1.38 (dt, 3H) ppm.

Step B: Preparation of ethyl5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylate

To a suspension of phenylhydrazine hydrochloride (6.15 g, 42.54 mmol) inEtOH (150 mL) was added ethyl 3-cyano-2-oxobutanoate (6.6 g, 42.54mmol). The reaction mixture was heated to reflux for 16 hours, thencooled to ambient temperature. The reaction mixture was diluted withsaturated aqueous NaHCO₃ (50 mL), extracted with DCM (3×100 mL), and thecombined organic phases were dried (MgSO₄), filtered and concentratedunder vacuum. The crude product was purified by silica columnchromatography, eluting with 0-60% acetone in hexanes to afford theproduct as a yellow solid (7.1 g, 68% yield). MS (apci) m/z=246.1 (M+H).

Step C: Preparation of5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid

To a solution of ethyl5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylate (1.52 mg, 6.21 mmol)in THF (12 mL) and MeOH (6 mL) was added LiOH (2M aq, 9.31 mL, 18.6mmol). The reaction mixture was stirred at ambient temperature for 19hours, then partially concentrated under reduced pressure, thenneutralized with 6M HCl (3.2 mL), extracted with 10:90 MeOH/DCM (3×25mL), and the combined organic extracts were washed with brine (50 mL),dried (MgSO₄), filtered and concentrated to give the title compound as ayellow solid (1.3 g, 96% yield). MS (apci) m/z=218.1 (M+H).

Step D: Preparation of5-amino-N,4-dimethyl-1-phenyl-1H-pyrazole-3-carboxamide

To a solution of 5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid(223 mg, 1.02 mmol) in acetonitrile (10 mL) were added DIEA (0.71 mL,4.10 mmol), methanamine hydrochloride (138 mg, 2.05 mmol), DMF (2 mL),followed by addition of HATU (428 mg, 1.13 mmol). The reaction mixturewas stirred at ambient temperature for 19 hours and then partiallyconcentrated under reduced pressure. The mixture was purified byreverse-phase column chromatography, eluting with 5-60%acetonitrile/water to afford the title compound as a pale yellow solid(182 mg, 77% yield). MS (apci) m/z=231.1 (M+H).

Intermediate 11

Phenyl 4-methyl-3-(methylcarbamoyl)-1-phenyl-1H-pyrazol-5-ylcarbamate

Prepared by the method as described for Intermediate 1 using5-amino-N,4-dimethyl-1-phenyl-1H-pyrazole-3-carboxamide instead of3-methyl-1-phenyl-1H-pyrazol-5-amine. The crude material (75.6 mg,0.2158 mmol, 99.4% yield) was used without purification. MS (apci)m/z=351.1 (M+H).

Intermediate 12

1′,4-dimethyl-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-amine Step A: ethyl1-methyl-1H-pyrazole-4-carboxylate

To a 3000-mL three-necked flask was added ethyl 2-formyl-3-oxopropanoate(100 g, 694 mmol), followed by anhydrous 200-proof EtOH (694 mL) toobtain a clear yellowish solution. The reaction was cooled in an icebath to 5° C., and then methylhydrazine (35.8 mL, 680 mmol) was addeddropwise. A vigorous exotherm was observed during hydrazine addition andthe temperature was kept below 12° C. by controlling the addition rate.After the hydrazine addition was complete, the ice bath was removed, andthe reaction was allowed to stir at ambient temperature overnight. Thereaction was concentrated on a rotary evaporator to a crude orange oil.The crude was taken up in DCM and re-concentrated, then on high vacuumfor 2 days to yield the title compound as a tan orange oil (106 g, 99.1%yield).

Step B: 2-methyl-3-(1-methyl-1H-pyrazol-4-yl)-3-oxopropanenitrile

To a four-necked 5-liter round bottomed flask fitted with an overheadstirrer and addition funnel was charged LHMDS (1444 mL, 1444 mmol) (1.0Min THF). The solution was cooled in an acetone/dry ice bath (internaltemperature of −79° C.) under nitrogen, followed by slow addition ofpropiononitrile (103 mL, 1444 mmol) via dropping funnel. The mixture wasstirred at −80° C. for 90 minutes. A solution of ethyl1-methyl-1H-pyrazole-4-carboxylate (106 g, 688 mmol) in anhydrous THF(500 mL) was then introduced dropwise via an addition funnel (additiontime: about 45 minutes; internal temperature during addition remainedbelow −76° C.). After the addition was complete, the reaction wasallowed to slowly warm to ambient temperature and stirred overnight. Anorange glass deposited on the bottom of the flask. The organics weredecanted and the orange glass was dissolved in warm water. The aqueousmixture was washed with with ether (3×1000 mL). The aqueous phase wasthen pH-adjusted to 5 (pH paper) using concentrated HCl and saturatedbicarbarbonate solution The aqueous layer was extracted with DCM (3×1000mL). The combined organic extracts were dried over MgSO₄, filtered andconcentrated to yield2-methyl-3-(1-methyl-1H-pyrazol-4-yl)-3-oxopropanenitrile as an amberoil (92 g, 82% yield). MS (apci) m/z=162.1 (M−H).

Step C: 1′,4-dimethyl-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-amine

A 3 L, 3 necked round bottomed flask was charged with2-methyl-3-(1-methyl-1H-pyrazol-4-yl)-3-oxopropanenitrile (60 g, 368mmol) absolute anhydrous ethanol (1000 mL) and phenylhydrazinehydrochloride (58 g, 404 mmol) at ambient temperature to form ayellowish suspension. The reaction vessel was equipped with a watercondenser and refluxed (using a heating mantle) overnight. The reactionwas concentrated and 1M NaOH (1 L) was added and the solid was broken upand collected. The solid was washed with water and hexanes. A secondcrop crashed out in the filtrate and was collected. The combined solidswere crushed and triturated with ether (500 mL). The solid was collectedfiltration, washed with hexanes and air dried under vacuum to provide1′,4-dimethyl-1-phenyl-1H, 1′H-3,4′-bipyrazol-5-amine (93 g, 100%yield).

Step D: phenyl 1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-ylcarbamate

In a 3 L, round bottomed flask was charged with1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-amine (50 g, 197.4 mmol)and EtOAc (1000 mL) to obtain a clear brownish solution. To this wasadded NaOH (2M aq) (500 mL) in one portion to obtain a turbid mixture(both the aqueous and organic layers were clear but a precipitate wasobserved in between the two layers). After 3 minutes, phenylcarbonochloridate (74.29 mL, 592.2 mmol) was added slowly at ambienttemperature exotherm to 33° C. The reaction stirred at ambienttemperature for 2 hours. Additional phenyl carbonochloridate (10 mL) wasadded. After 30 minutes the organics were separated, washed with brineand concentrated under vacuum. The product was purified by silica gelchromatography (eluting with 75% ethyl acetate in hexanes) to providephenyl 1′,4-dimethyl-1-phenyl-1H, 1′H-3,4′-bipyrazol-5-ylcarbamate (60g, 81.4% yield).

Intermediate 13

phenyl (1′,4-dimethyl-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-yl)carbamate

A 3 L, round bottomed flask was charged with1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-amine (50 g, 197.4 mmol)and EtOAc (1000 mL) to obtain a clear brownish solution. To this wasadded aqueous NaOH (2M; 500 mL) in one portion to obtain a turbidmixture (the aqueous and organic layers were clear, but a precipitatewas observed in between the two layers). After 3 minutes, phenylcarbonochloridate (74.29 mL, 592.2 mmol) was added slowly at ambienttemperature (the temperature of the reaction mixture increased to 33° C.during the addition). The reaction stirred at ambient temperature for 2hours. Additional phenyl carbonochloridate (10 mL) was added. After 30minutes the organics layers were separated, washed with brine andconcentrated under vacuum. The residue was purified by silica gelchromatography (eluting with 75% ethyl acetate in hexanes) to providephenyl 1′,4-dimethyl-1-phenyl-1H, 1′H-3,4′-bipyrazol-5-ylcarbamate (60g, 81.4% yield).

Intermediate 14

phenyl (2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)carbamate

A suspension of 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine(6.0 g, 30.11 mmol) in EtOAc (250 mL) was first cooled in ice bath,followed by addition of NaOH (2N aq, 30.11 mL, 60.23 mmol) in oneportion and then PhOCOCl (6.800 mL, 54.20 mmol) drop-wise. The reactionwas warmed up to ambient temperature and stirred for 18 hours. Thereaction mixture was diluted with EtOAc (100 mL) and phase-separated.The organic layer was washed with water (2×150 mL) and brine (150 mL),dried (MgSO₄), filtered and concentrated. The crude was taken up in DCMand concentrated to dryness. The crude solid was triturated withether/hexanes (2:1, 2×100 mL), filtered and dried, to provide theproduct as an off-white solid (7.4 g, 77% yield). MS (apci) m/z=320.1(M+H).

Intermediate 15

3,4-dimethyl-1-phenyl-1H-pyrazol-5-amine

To a solution of 2-methyl-3-oxobutanenitrile (295 mg, 3.038 mmol) inEtOH (40 mL) were added HCl (5-6M in iPrOH, 0.6 mL) and phenylhydrazine(0.299 mL, 3.038 mmol). The reaction mixture was heated at reflux for 17hours, then cooled to ambient temperature. The reaction mixture wasdiluted with saturated aqueous NaHCO₃ (20 mL), extracted with DCM (2×25mL), and the combined organic phases were dried (MgSO₄), filtered andconcentrated. The crude product was purified by silica columnchromatography, eluting with 0-3% MeOH/DCM to yield the product as a tansolid (555 mg, 97% yield). MS (apci) m/z=188.2 (M+H).

Intermediate 16

phenyl 3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl carbamate

Prepared by the method as described for Intermediate 1, using3,4-dimethyl-1-phenyl-1H-pyrazol-5-amine instead of3-methyl-1-phenyl-1H-pyrazol-5-amine. The crude product (0.933 g, 3.036mmol, quantitative yield) was used without purification. MS (apci)m/z=308.1 (M+H).

SYNTHETIC EXAMPLES

Table 1 provides a list of commercially available compounds that wereused in the synthesis of intermediates and examples.

TABLE 1 Structure Vendor/Catalog # CAS #

Ryan Scientific, Inc., EN300-14400 89399-92-8

Combi-Blocks, Inc., HI-1327 5346-56-5

Aldrich/24,782-0 2217-40-5

Lancaster Synthesis Inc./17022 23357-52-0

Aldrich/668,818 21966-60-9

ChemBridge/4102674 52373-02-1

J & W PharmLab, LLC/20-1070 53981-38-7

Matrix Scientific/021506 N/A

Activate Scientific/D4046 147663-00-1

Activate Scientific/A52094G1 N/A

AstaTech, Inc./52240 486453-50-3

Ryan Scientific, Inc./EN400-13090 N/A

APAC Pharmaceutical/552625 253185-43-2

Ubichem plc/cat #UB-10298 N/A

Maybridge/MO 01275 32281-97-3

CiVenti Chem/CV-1709 166978-46-7

Key Organics Ltd./SS-3938 N/A

Oakwood Products,Inc./008563 88754-96-5

Chemgenx, LLC/CX-01571 113209-68-0

Carbocore/CH-0014 49660-57-3

Enamine/EN300-31791 116140-19-3

AstaTech, Inc./52240 486453-50-3 N/A = Not available

Table 1 provides a list of commercially available pyrazole intermediatescan be used in the synthesis of compounds described in the Examples.

TABLE 1 Pyrazole Vendor/Catalog # CAS #

Oakwood, 021512 126208-61-5

Array BioPharma, A1075-0 N/A

Maybridge, GK03066 1192-21-8

Ryan Scientific, EN300-14400 89399-92-8

Oakwood, 021516 N/A

Alfa Aesar, AAB20095-06 118430-73-2

Aldrich, 532223 3524-32-1

Accela ChemBio Chem Co, SY003755 876299-97-7

ChemImpex, 18122 778611-16-8

Oakwood, 017105 175137-45-8

Alfa Aesar, AAB20464-06 5356-71-8

Aldrich, 541001 1131-18-6

Alfa Aesar, AAA15754-06 10199-50-5

TCI America, A0174 826-85-7

Oakwood, 023890 N/A

J & W Pharmalab, 68-0035S 1187931-80-1

VWR, EN300-09508 N/A

ChemBridge, 4019184 885529-68-0

ChemBridge, 4001950 N/A

ChemImpex, 19156 337533-96-7

ChemImpex, 19155 898537-77-4

ChemBridge, 4006072 N/A

Oakwood, 005982 5346-56-5

ChemImpex, 18771 182923-55-3

Maybridge, KM00278 118430-74-3

Maybridge, KM00835 118430-78-7

ChemBridge, 4015288 N/A

ChemBridge, 4015289 N/A

Matrix, 020274 N/A

Matrix, 019183 N/A

Maybridge, KM 04038 126417-82-1

ChemBridge, 4001950 N/A

Lancaster, AAA17470-06 7152-40-1

ChemBridge, 4010196 91642-97-6

VWR, AAA13296-14 16078-71-0 N/A = Not available

Intermediate P1

Ethyl 3-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)benzoate

To a suspension of ethyl 3-hydrazinylbenzoate hydrochloride (500 mg,2.31 mmol) in EtOH (20 mL) was added 4,4-dimethyl-3-oxopentanenitrile(318 mg, 2.54 mmol). The reaction mixture was heated to reflux for 18hours, then cooled to ambient temperature and concentrated in vacuo. Thecrude product was purified by silica column chromatography, eluting with0-5% MeOH/DCM to yield the product as a yellow oil (154 mg, 23% yield).MS (apci) m/z=288.2 (M+H).

The compounds in Table 2 were prepared by the method as described forIntermediate P1, substituting 4,4-dimethyl-3-oxopentanenitrile with theappropriate cyanoketone and ethyl 3-hydrazinylbenzoate hydrochloridewith the appropriate hydrazine.

TABLE 2 Intermediate # Structure Data P2 

MS (apci) m/z = 188.2 (M + H) P3 

MS (apci) m/z = 218.1 (M + H) P4 

MS (apci) m/z = 218.2 (M + H) P5 

MS (apci) m/z = 188.2 (M + H) P6 

MS (apci) m/z = 214.2 (M + H) P7 

MS (apci) m/z = 188.2 (M + H) P8 

MS (apci) m/z = 301.0 (M + H) P9 

MS (apci) m/z = 218.1 (M + H) P10

MS (apci) m/z = 175.2 (M + H) P11

MS (apci) m/z = 237.3 (M + H) P12

MS (apci) m/z = 188.2 (M + H) P13

MS (apci) m/z = 188.2 (M + H) P14

MS (apci) m/z = 188.2 (M + H) P15

MS (apci) m/z = 204.2 (M + H) P16

MS (apci) m/z = 204.2 (M + H) P17

MS (apci) m/z = 199.0 (M + H) P18

MS (apci) m/z = 199.1 (M + H) P19

MS (apci) m/z = 192.2 (M + H) P20

MS (apci) m/z =192.2 (M + H) P21

MS (apci) m/z = 232.2 (M + H) P22

MS (apci) m/z = 204.2 (M + H) P23

MS (apci) m/z = 206.1 (M + H)

Intermediate P101

2-(1-methyl-1H-pyrazol-4-yl)-2,4,5,6-tetrahydrocyclopenta-[c]pyrazol-3-amineStep A: Preparation of di-tert-butyl1-(1-methyl-1H-pyrazol-4-yl)hydrazine-1,2-dicarboxylate

To a solution of 4-bromo-1-methyl-1H-pyrazole (1.93 mL, 18.6 mmol) inether (37.3 mL) cooled to −78° C. was added nBuLi (23.3 mL, 37.3 mmol).After stirring at −78° C. for 30 minutes, a solution of di-t-butylazodicarboxylate (4.29 g, 18.6 mmol) in Et₂O (37.3 mL, 18.6 mmol) wasadded dropwise. After 1 hour, the reaction mixture was warmed up to −20OC and quenched with ice. After warming to ambient temperature, themixture was filtered and rinsed with Et₂O. The resulting solid was takenup in a mixture of DCM and water, and the mixture was phase separated.The organic layer was dried with MgSO₄, filtered and concentrated invacuo to afford the first batch of product as a white solid (1.64 g, 28%yield). A second batch of product was recovered from the filtrate bysilica column chromatography, eluting with 40-60% hexanes/EtOAc (0.51 g,8.8% yield). MS (apci) m/z=313.0 (M+H).

Step B: Preparation of2-(1-methyl-1H-pyrazol-4-yl)-2,4,5,6-tetrahydrocyclopenta-[c]pyrazol-3-amine

To a solution of di-tert-butyl1-(1-methyl-1H-pyrazol-4-yl)hydrazine-1,2-dicarboxylate (103 mg, 0.330mmol) in EtOH (1.65 mL, 0.330 mmol) was added concentrated HCl (137 μL,1.65 mmol). The mixture was stirred at ambient temperature for 5minutes, then cooled in an ice bath followed by addition of2-oxocyclopentanecarbonitrile (36.0 mg, 0.330 mmol). After stirring for5 minutes, the reaction mixture was warmed to ambient temperatureovernight. The reaction mixture was concentrated and partitioned inwater and DCM. After phase-separation, the aqueous layer was basified(pH 10) and then extracted with DCM (3×10 mL). The combined organicextracts were dried with MgSO₄, filtered and concentrated in vacuo. Thecrude material was purified by reverse-phase column chromatography,eluting with 0-100% acetonitrile/water to afford the product as a yellowsolid (4.5 mg, 6.7% yield). MS (apci) m/z=204.1 (M+H).

Intermediate P102

3-tert-butyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine Step A:Preparation of (tetrahydro-2H-pyran-4-yl)hydrazine hydrochloride

A suspension of dihydro-2H-pyran-4(3H)-one (2.00 g, 20.0 mmol) andtert-butyl hydrazinecarboxylate (2.64 g, 20.0 mmol) in hexanes (20.0 mL)was refluxed for 2 hours. After cooling, BH₃-THF complex (20.0 mL, 20.0mmol) was added and the reaction mixture was stirred for 1 hour. Themixture was then treated with 4 N HCl in dioxane (20.0 mL, 79.9 mmol),followed by 3 drops of water. After stirring at ambient temperature for1 hour, the reaction mixture was filtered and rinsed with EtOAc toafford the product as a solid (2.39 g, 78.4% yield). MS (apci) m/z=117.0(M+H).

Step B: Preparation of3-tert-butyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine

Prepared by the method as described in for the preparation ofIntermediate P1, substituting (tetrahydro-2H-pyran-4-yl)hydrazinedihydrochloride for ethyl 3-hydrazinylbenzoate hydrochloride to yieldthe product as a yellow oil (0.472 g, 99.9% yield). MS (apci) m/z=224.1(M+H).

Intermediate P103

2-(pyridin-2-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine Step A:Preparation of 2-(2-(pyridin-2-yl)hydrazono)cyclopentane-carbonitrile

A solution of 2-hydrazinylpyridine (0.200 g, 1.83 mmol) and2-oxocyclopentanecarbonitrile (0.200 g, 1.83 mmol) in MeOH (9.16 mL) wastreated with concentrated HCl (0.764 mL, 9.16 mmol) and refluxed for 16hours. The reaction mixture was concentrated in vacuo, and thenpartitioned in water and DCM. After phase-separation, the aqueous layerwas washed with DCM, basified (saturated NaHCO₃, pH 10), and extractedwith DCM. The combined organic layers were dried with MgSO₄, filteredand concentrated. The crude material was purified by silica columnchromatography, eluting with 100% EtOAc to afford the product (0.289 g,78.6% yield). MS (apci) m/z=201.2 (M+H).

Step B: Preparation of2-(pyridin-2-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine

A solution of 2-(2-(pyridin-2-yl)hydrazono)cyclopentanecarbonitrile(0.243 g, 1.21 mmol) in EtOH (6.06 mL, 1.21 mmol) was treated with 6 MHCl (0.202 mL, 1.21 mmol) and refluxed for 3 days. After removal of thesolvent, the crude residue was diluted in water, basified (saturatedNaHCO₃, pH 10) and extracted with DCM. The combined organic layers weredried with MgSO₄, filtered and concentrated. The crude material waspurified by silica column chromatography, eluting with 50% EtOAc/hexanesto afford the product (0.198 g, 81.6% yield). MS (apci) m/z=201.2 (M+H).

Intermediate P104

2-(pyridin-3-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine

Prepared by the method described above for Intermediate P103,substituting 3-hydrazinylpyridine for 2-hydrazinyl pyridine to affordthe title product. MS (apci) m/z=201.1 (M+H).

Intermediate P105

6,6-dimethyl-2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amineStep A: Preparation of 5-chloro-2,2-dimethylpentanenitrile

Isobutyronitrile (1.38 g, 20.0 mmol) and 1-bromo-3-chloropropane (3.46g, 22.0 mmol) were sequentially added to a 1 M solution of lithiumbis(trimethylsilyl)amide (20.0 mL, 20.0 mmol) while stirring. Afterstirring at 70° C. for 16 hours, the reaction mixture was quenched withwater then extracted with DCM. The combined organic layers were driedwith MgSO₄, filtered and concentrated in vacuo to afford5-chloro-2,2-dimethylpentanenitrile (2.91 g, 100% yield). ¹H NMR (CDCl₃)δ 3.57-3.61 (m, 2H), 1.94-2.02 (m, 2H), 1.67-1.72 (m, 2H), 1.37 (s, 6H).

Step B: Preparation of 2,2-dimethylhexanedinitrile

A suspension of 5-chloro-2,2-dimethylpentanenitrile (2.91 g, 20.0 mmol)and NaCN (1.57 g, 32.0 mmol) in DMF (20.0 mL) and water (1 mL) washeated at 100° C. for 16 hours. After cooling, the reaction mixture wasdiluted with water and refluxed for 30 minutes, then cooled, poured intowater and stirred for 3 hours. The solution was then extracted withEt₂O. The combined Et₂O extracts were washed with H₂O, dried with MgSO₄,filtered and concentrated in vacuo to afford the product (2.20 g, 80.7%yield). ¹H NMR (CDCl₃) δ 2.42-2.47 (m, 2H), 1.83-1.92 (m, 2H), 1.67-1.72(m, 2H), 1.39 (s, 6H).

Step C: Preparation of 3,3-dimethyl-2-oxocyclopentanecarbonitrile

A suspension of KOtBu (0.511 g, 4.55 mmol) in toluene (18.4 mL) wastreated a toluene (2.0 mL) solution of 2,2-dimethylhexanedinitrile (1.00g, 7.34 mmol) and heated at 80° C. for 2 hours. The reaction mixture wasthen cooled to ambient temperature and quenched with water. The mixturewas separated and the organic layer was stirred in 2 N HCl (20 mL) for16 hours. The mixture was separated and the organic layer dried withMgSO₄, filtered and concentrated in vacuo to a yellow-white solid. Thecrude solid was purified by silica column chromatography, eluting with10-40% EtOAc/hexanes, to afford the product (0.250 g, 24.8% yield). ¹HNMR (CDCl₃) δ 3.20-3.26 (m, 1H), 2.38-2.47 (m, 1H), 2.14-2.25 (m, 1H),1.97-2.05 (m, 1H), 1.74-1.83 (m, 1H), 1.14 (s, 6H).

Step D: Preparation of6,6-dimethyl-2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine

Prepared by the method as described for Intermediate P1, substitutingphenylhydrazine for ethyl 3-hydrazinylbenzoate hydrochloride and3,3-dimethyl-2-oxocyclopentanecarbonitrile for4,4-dimethyl-3-oxopentanenitrile to afford the product (0.192 g, 46.2%yield) as a yellow solid. MS (apci) m/z=228.2 (M+H).

Intermediate P106

7,7-dimethyl-2-phenyl-4,5,6,7-tetrahydro-2H-indazol-3-amine Step A:Preparation of 2,2-dimethylheptanedinitrile

Prepared by the method as described for Intermediate P105, Steps A andB, substituting 1-bromo-4-chlorobutane for 1-bromo-3-chloropropane toyield the product (2.21 g, 73.7% yield). ¹H NMR (CDCl₃) δ 2.37-2.42 (m,2H), 1.53-1.77 (m, 6H), 1.36 (s, 6H).

Step B: Preparation of 3,3-dimethyl-2-oxocyclohexanecarbonitrile

A suspension of KOtBu (0.463 g, 4.13 mmol) in toluene (16.6 mL) wastreated with a solution of 2,2-dimethylheptanedinitrile (1.00 g, 6.66mmol) in toluene (2.0 mL) and heated at 80° C. for 48 hours. Aftercooling to ambient temperature, the reaction mixture was quenched withwater and phase-separated, and the organic layer was stirred with 2 NHCl (20 mL) for 16 hours. After phase-separation, the organic layer wasdried with MgSO₄, filtered and concentrated in vacuo. The crude materialwas purified by silica column chromatography, eluting with 10-20%EtOAc/hexanes to afford the product (0.374 g, 37.2% yield). ¹H NMR(CDCl₃) δ 3.72-3.78 (m, 1H), 2.42-2.50 (m. 1H), 1.78-2.04 (m, 4H),1.60-1.70 (m, 1H), 1.21 (s, 3H), 1.16 (s, 3H).

Step C: Preparation of7,7-dimethyl-2-phenyl-4,5,6,7-tetrahydro-2H-indazol-3-amine

Prepared by the method as described for Intermediate P1, substitutingphenylhydrazine for ethyl 3-hydrazinylbenzoate hydrochloride and3,3-dimethyl-2-oxocyclohexanecarbonitrile for4,4-dimethyl-3-oxopentanenitrile to yield the product as an off-whitesolid (0.490 g, 54.2% yield, 66% purity). MS (apci) m/z=242.2 (M+H).

Intermediate P107

3-isopropyl-4-methyl-1-phenyl-1H-pyrazol-5-amine Step A: Preparation of2,4-dimethyl-3-oxopentanenitrile

To a solution of propiononitrile (518 mg, 9.40 mmol) in THF (50 mL, 7.83mmol) at −78° C. under N₂ was slowly added lithiumbis(trimethylsilyl)amide (1M in THF) (7.83 mL, 7.83 mmol). After 30minutes, methyl isobutyrate (0.898 mL, 7.83 mmol) was added dropwise,and the reaction mixture was warmed to 0° C. A yellow precipitateformed, the reaction mixture was stirred for 1 hour, then diluted withH₂O (50 mL) to dissolve the solids. The mixture was extracted with Et₂O(25 mL), and the basic aqueous phase was acidified with 2M HCl (5 mL)and extracted with Et₂O (2×50 mL). The combined organic phases werewashed with brine (50 mL), dried with MgSO₄, filtered, and concentratedto afford the product (421 mg, 42.9% yield)

Step B: Preparation of 3-isopropyl-4-methyl-1-phenyl-1H-pyrazol-5-amine

Prepared by the method as described for Intermediate P1, substitutingphenyl hydrazine for ethyl 3-hydrazinylbenzoate hydrochloride and4,4-dimethyl-3-oxopentanenitrile with 2,4-dimethyl-3-oxopentanenitrileto yield the product as a yellow syrup (0.587 g, 81.1% yield). MS (apci)m/z=216.2 (M+H).

Intermediate P108

2-phenyl-4,6-dihydro-2H-furo[3,4-c]pyrazol-3-amine Step A: Preparationof 4-oxotetrahydrofuran-3-carbonitrile

To a suspension of KOtBu (996.6 mg, 8.881 mmol) in THF (640.4 mg, 8.881mmol) cooled to 0° C. was added dropwise methyl 2-hydroxyacetate (675.7μL, 8.881 mmol) and stirred for 10 minutes. The acrylonitrile (589.1 μL,8.881 mmol) was then added and the reaction stirred at ambienttemperature. After 3 hours, the reaction was diluted with H₂O (50 mL),then extracted with Et₂O (25 mL) to remove any starting ester. The basicaqueous phase was acidified with 2M HCl (5 mL), then extracted with Et₂O(2×50 mL). The combined organic phases were dried with MgSO₄, filtered,and concentrated to afford a light brown oil (446 mg, 45.2% yield). ¹HNMR (CDCl₃) δ 4.63 (t, 1H), 4.24 (t, 1H), 4.14 (d, 1H), 4.02 (d, 1H),3.57 (t, 1H).

Step B: Preparation of2-phenyl-4,6-dihydro-2H-furo[3,4-c]pyrazol-3-amine

Prepared by the method as described for Intermediate P1, substitutingphenyl hydrazine for ethyl 3-hydrazinylbenzoate hydrochloride and4,4-dimethyl-3-oxopentanenitrile with4-oxotetrahydrofuran-3-carbonitrile to yield the product as areddish-brown syrup (182 mg, 22.5% yield). MS (apci) m/z=202.1 (M+H).

Intermediate P109

3-(methoxymethyl)-1-phenyl-1H-pyrazol-5-amine Step A: Preparation of4-methoxy-3-oxobutanenitrile

To a solution of methyl 2-methoxyacetate (0.4753 mL, 4.803 mmol) in THF(20 mL, 4.803 mmol) at −78° C. under N₂ was added acetonitrile (0.3033mL, 5.763 mmol), followed by lithium bis(trimethylsilyl)amide (1M inTHF) (4.803 mL, 4.803 mmol). After stirring 1 hour, the reaction mixturewas warmed to 0° C. and stirred for 1 hour. The reaction mixture wasthen diluted with H₂O (25 mL), washed with Et₂O (25 mL), thenneutralized with 2 M HCl (1.5 mL). This was extracted with Et₂O (2×25mL) and the combined organic phases were washed with brine (25 mL),dried with MgSO₄, filtered, and concentrated to afford the product (169mg, 31.1% yield). ¹H NMR (CDCl₃) δ 4.09 (s, 2H), 3.66 (s, 2H), 3.46 (s,3H)

Step B: Preparation of 3-(methoxymethyl)-1-phenyl-1H-pyrazol-5-amine

Prepared by the method as described for Intermediate P1, substitutingphenyl hydrazine for ethyl 3-hydrazinylbenzoate hydrochloride and4,4-dimethyl-3-oxopentanenitrile with 4-methoxy-3-oxobutanenitrile toyield the product as a pale yellow residue (6.0 mg, 2.0% yield). MS(apci) m/z=204.0 (M+H).

Intermediate P110

3-(methoxymethyl)-4-methyl-1-phenyl-1H-pyrazol-5-amine

Prepared according to the method as described for Intermediate P109,replacing acetonitrile with propionitrile to afford the product as anorange residue. MS (apci) m/z=218.0 (M+H).

Intermediate P111

2-(5-amino-1-phenyl-1H-pyrazol-3-yl)-2-methylpropan-1-ol Step A:Preparation of methyl3-(tert-butyldimethylsilyloxy)-2,2-dimethyl-propanoate

Methyl 3-hydroxy-2,2-dimethylpropanoate (1.000 g, 7.567 mmol), TBDMS-Cl(1.140 g, 7.567 mmol) and imidazole (0.5666 g, 8.323 mmol) weredissolved in DMF (5 mL, 7.567 mmol) and stirred at ambient temperatureovernight. The reaction mixture was diluted with H₂O (25 mL) andextracted with EtOAc (2×25 mL). The combined organic phases were washedwith brine (25 mL), dried with MgSO₄, filtered and concentrated toafford the product (1.92 g, 103% yield). ¹H NMR (CDCl₃) δ 3.66 (s, 3H),3.57 (s, 2H), 1.15 (s, 6H), 0.87 (s, 9H), 0.02 (s, 6H).

Step B: Preparation of5-(tert-butyldimethylsilyloxy)-4,4-dimethyl-3-oxopentanenitrile

Prepared according to the method described for Intermediate P109,replacing methyl 2-methoxyacetate with methyl3-(tert-butyldimethylsilyloxy)-2,2-dimethylpropanoate to afford theproduct as a pale yellow residue. ¹H NMR (CDCl₃) δ 3.70 (s, 2H), 3.55(s, 2H), 1.15 (s, 6H), 0.89 (s, 9H), 0.06 (s, 6H).

Step C: Preparation of2-(5-amino-1-phenyl-1H-pyrazol-3-yl)-2-methylpropan-1-ol

Prepared by the method as described for Intermediate P1, substitutingphenyl hydrazine for ethyl 3-hydrazinylbenzoate hydrochloride and4,4-dimethyl-3-oxopentanenitrile with methyl3-(tert-butyldimethylsilyloxy)-2,2-dimethylpropanoate to yield theproduct as yellow syrup (74 mg, 66% yield). MS (apci) m/z=232.2 (M+H).

Intermediate P112

2-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-2-methylpropan-1-ol

Prepared according to the method described for Intermediate P111,replacing acetonitrile with propionitrile to afford the product as ayellow residue. MS (apci) m/z=246.2 (M+H).

Intermediate P113

3-(3-methoxypropyl)-4-methyl-1-phenyl-1H-pyrazol-5-amine

Prepared according to the method described for Intermediate P109,replacing methyl 2-methoxyacetate with methyl 4-methoxybutanoate andreplacing acetonitrile with propionitrile in Step A to afford theproduct as an orange-brown syrup. MS (apci) m/z=246.1 (M+H).

Intermediate P114

1,1′-dimethyl-1H, 1′H-3,4′-bipyrazol-5-amine Step A: Preparation of3-(1-methyl-1H-pyrazol-4-yl)-3-oxopropanenitrile

A solution of ethyl 1-methyl-1H-pyrazole-4-carboxylate (500 mg, 3.24mmol), toluene (7.50 mL, 70.4 mmol), and acetonitrile (346 μL, 6.49mmol) was treated in one portion with KOtBu (1092 mg, 9.73 mmol) to givea hazy solution. The reaction was allowed to stir at ambient temperaturefor one hour, and was determined to be complete by HPLC analysis. Themixture was treated with water (7.5 mL) and stirred for 1 minute, thenacidified with 3M HCl (3027 μL, 9.08 mmol) to pH 5.5-6. The aqueouslayer was extracted with ethyl acetate (3×5 mL) and the combined organicextracts were concentrated in vacuo to give a yellow viscous oil, whichcompletely solidified upon placing under high vacuum to afford theproduct (102 mg, 21.1% yield). ¹H NMR (CDCl₃) δ 8.02 (s, 1H), 7.94 (s,1H), 3.98 (s, 3H), 3.82 (s, 2H)

Step B: Preparation of 1,1′-dimethyl-1H, 1′H-3,4′-bipyrazol-5-amine

Prepared by the method as described for Intermediate P1, substitutingmethyl hydrazine for ethyl 3-hydrazinylbenzoate hydrochloride andreplacing 4,4-dimethyl-3-oxopentanenitrile with3-(1-methyl-1H-pyrazol-4-yl)-3-oxopropanenitrile to yield the product asan ivory white solid (45 mg, 44.6% yield). MS (apci) m/z=178.1 (M+H).

Intermediate P115

4-chloro-1,3-diphenyl-1H-pyrazol-5-amine

To a solution of 1,3-diphenyl-1H-pyrazol-5-amine (Table 1; 0.100 g,0.425 mmol) in acetonitrile (2 mL) was added N-chlorosuccinimide (0.0568g, 0.425 mmol). The pale yellow solution was stirred at ambienttemperature for 3 hours, then concentrated in vacuo and purified bysilica column chromatography eluting with 20% EtOAc/Hexanes to affordthe product as a light brown oil (0.10 g, 87% yield). MS (apci)m/z=270.0 (M+H).

Intermediate P116

4-bromo-1,3-diphenyl-1H-pyrazol-5-amine

Prepared according to the procedure described for Intermediate P115,substituting N-chloro succinimide with N-bromo-succinimide. MS (apci)m/z=313.9 (M+H).

Intermediate P117

4-chloro-3-methyl-1-phenyl-1H-pyrazol-5-amine

Prepared according to the procedure described for Intermediate P115,substituting 1,3-diphenyl-1H-pyrazol-5-amine with3-methyl-1-phenyl-1H-pyrazol-5-amine. MS (apci) m/z=207.9 (M+H).

Intermediate P118

4-bromo-3-methyl-1-phenyl-1H-pyrazol-5-amine

Prepared according to the procedure described for Intermediate P117,substituting N-chloro succinimide with N-bromo-succinimide. MS (apci)m/z=251.9 (M+H).

Intermediate P119

4-chloro-1-methyl-3-phenyl-1H-pyrazol-5-amine

Prepared according to the procedure described for Intermediate P115,substituting 1,3-diphenyl-1H-pyrazol-5-amine with1-methyl-3-phenyl-1H-pyrazol-5-amine (Table 1). MS (apci) m/z=208.0(M+H).

Intermediate P120

4-bromo-1-methyl-3-phenyl-1H-pyrazol-5-amine

Prepared according to the procedure described for Intermediate P119,substituting N-chloro succinimide with N-bromo-succinimide. MS (apci)m/z=251.9 (M+H).

Intermediate P121

1-methyl-3-(4-(methylthio)phenyl)-1H-pyrazol-5-amine Step A: Preparationof 3-(4-(methylthio)phenyl)-3-oxopropanenitrile

To a suspension of NaH (60% in mineral oil) (154 mg, 3.84 mmol) indioxane (25.0 mL, 2.74 mmol) was added acetonitrile (0.217 mL, 4.12mmol). The reaction mixture was stirred at ambient temperature for 30minutes, then treated with methyl 4-(methylthio)benzoate (500 mg, 2.74mmol) and heated to reflux for 15 hours. The suspension was cooled, thendiluted with water (25 mL) and washed with Et₂O (25 mL). The aqueouslayer was neutralized with 2M HCl (1.8 mL) and extracted with Et₂O (2×25mL). The combined organic phases were washed with brine (25 mL), driedwith MgSO₄, filtered and concentrated in vacuo. The resultant residuewas purified by silica column chromatography eluting with 0-5% MeOH/DCMto afford the product (317 mg, 60.4% yield). ¹H NMR (CDCl₃) δ 7.82 (d,2H), 7.30 (d, 2H), 4.02 (s, 2H), 2.54 (s, 3H).

Step B: Preparation of1-methyl-3-(4-(methylthio)phenyl)-1H-pyrazol-5-amine

Prepared by the method as described in Intermediate P1, substitutingmethylhydrazine for ethyl 3-hydrazinylbenzoate hydrochloride andsubstituting 3-(4-(methylthio)phenyl)-3-oxopropanenitrile for4,4-dimethyl-3-oxopentanenitrile to yield the product as a yellow solid(0.307 g, 96.7% yield). MS (apci) m/z=220.0 (M+H).

Intermediate P122

2-(5-amino-1-phenyl-1H-pyrazol-3-yl)-2-methylpropanenitrile

Prepared according to the procedure for Intermediate P121, substitutingmethyl 4-(methylthio)benzoate with ethyl 2-cyano-2-methylpropanoate inStep A and phenyl hydrazine hydrochloride for methyl hydrazine in StepB. MS (apci) m/z=227.1 (M+H).

Intermediate P123

3-(4-(2-methoxyethoxy)phenyl)-1-methyl-1H-pyrazol-5-amine Step A:Preparation of 3-(4-(benzyloxy)phenyl)-3-oxopropanenitrile

Prepared according to the procedure described for Intermediate P121,substituting methyl 4-(methylthio)benzoate with methyl4-(benzyloxy)benzoate in Step A. ¹H NMR (CDCl₃) δ 7.90 (d, 2H), 7.42 (m,4H), 7.37 (m, 1H), 7.05 (d, 2H), 5.16 (s, 2H), 4.00 (s, 2H).

Step B: Preparation of3-(4-(benzyloxy)phenyl)-1-methyl-1H-pyrazol-5-amine

Prepared by the method as described for Intermediate P1, substitutingmethylhydrazine for ethyl 3-hydrazinylbenzoate hydrochloride and3-(4-(benzyloxy)phenyl)-3-oxopropanenitrile for4,4-dimethyl-3-oxopentanenitrile to yield the product as a yellow solid.MS (apci) m/z=280.1 (M+H).

Step C: Preparation of 4-(5-amino-1-methyl-1H-pyrazol-3-yl)phenol

To a solution of 3-(4-(benzyloxy)phenyl)-1-methyl-1H-pyrazol-5-amine (47mg, 0.17 mmol) in EtOH (5.0 mL) was added 5% Pd/C (9.0 mg, 0.0084 mmol)and stirred under a H₂ balloon for 17 hours. The reaction mixture wasfiltered through Celite®, rinsed with EtOH and concentrated in vacuo toafford the product (28 mg, 88% yield). MS (apci) m/z=190.1 (M+H).

Step D: Preparation of3-(4-(2-methoxyethoxy)phenyl)-1-methyl-1H-pyrazol-5-amine

To a solution of 4-(5-amino-1-methyl-1H-pyrazol-3-yl)phenol (14 mg,0.074 mmol) in DMSO (0.50 mL, 7.0 mmol) was added Cs₂CO₃ (48 mg, 0.15mmol) and 1-bromo-2-methoxyethane (9.7 μL, 0.10 mmol). The reactionmixture was stirred for 16 hours, then diluted with water (10 mL) andextracted with DCM (3×10 mL). The combined organic extracts were washedwith brine (10 mL), dried with MgSO₄, filtered and concentrated toafford the crude product (22 mg, 120% yield). The crude product was usedwithout purification in subsequent steps. MS (apci) m/z=248.0 (M+H).

Intermediate P124

1′-methyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-amine

Prepared according to the procedure described for Intermediate P114,substituting methylhydrazine with phenylhydrazine in Step B. MS (apci)m/z=240.0 (M+H).

Intermediate P125

4-methoxy-3-methyl-1-phenyl-1H-pyrazol-5-amine

Prepared according to the procedure for Intermediate P121, substitutingmethyl 4-(methylthio)benzoate with ethyl acetate and substitutingacetonitrile with 2-methoxyacetonitrile in Step A and phenyl hydrazinehydrochloride for methyl hydrazine in Step B. MS (apci) m/z=204.0 (M+H).

Intermediate P126

(5-amino-4-methyl-l-phenyl-1H-pyrazol-3-yl)methanol

Prepared according to the procedure for Intermediate P112, substitutingmethyl 3-hydroxy-2,2-dimethylpropanoate with ethyl 2-hydroxyacetate inStep A. MS (apci) m/z=204.1 (M+H).

Intermediate P127

2-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)ethanol

Prepared according to the procedure for Intermediate P112, substitutingmethyl 3-hydroxy-2,2-dimethylpropanoate with methyl 3-hydroxypropanoatein Step A. MS (apci) m/z=218.0 (M+H).

Intermediate P128

3-(2-methoxyethyl)-4-methyl-1-phenyl-1H-pyrazol-5-amine Step A:Preparation of 5-methoxy-2-methyl-3-oxopentanenitrile

To a suspension of NaNH₂ (50 wt % suspension in toluene) (330 mg, 4.23mmol) in THF (25 mL, 4.23 mmol) under N₂ at −78° C. was addedpropiononitrile (0.448 mL, 6.35 mmol), and the reaction mixture wasstirred for 30 minutes. Methyl 3-methoxypropanoate (0.495 mL, 4.23 mmol)was added and the reaction mixture was stirred at −78° C. for 1 hour,then at 0° C. for 2.5 hours. The reaction mixture was diluted with H₂O(25 mL) and washed with Et₂O (25 mL). The basic aqueous phase wasneutralized with 2M HCl (1.6 mL), then extracted with Et₂O (3×25 mL).The combined organic phases were washed with brine (25 mL), dried withMgSO₄, filtered, and concentrated to afford the crude product as a palegreenish oil (171 mg). The crude mixture was taken directly to the nextstep.

Step B: Preparation of3-(2-methoxyethyl)-4-methyl-1-phenyl-1H-pyrazol-5-amine

Prepared by the method as described for Intermediate P1, substituting5-methoxy-2-methyl-3-oxopentanenitrile for4,4-dimethyl-3-oxopentanenitrile and substituting phenylhydrazinehydrochloride for ethyl 3-hydrazinylbenzoate hydrochloride to yield theproduct as a yellow solid (56 mg, 20% yield). MS (apci) m/z=232.0 (M+H).

Intermediate P129

Phenyl(5-oxido-2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-yl)carbamate

A THF (4 mL) solution of phenyl2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-ylcarbamate (IntermediateP130, Step B; 50 mg, 0.15 mmol) was cooled to −50° C. with an externaldry-ice/MeCN bath and treated with a THF (2 mL) solution of3-chlorobenzoperoxoic acid (33 mg, 0.13 mmol). After stirring for 1hour, the mixture was quenched with Na₂S₂O₃ and water, extracted withEtOAc, washed with NaHCO₃ and brine, dried with MgSO₄, filtered, andconcentrated to give the product which was directly used in next stepwithout further purification. MS (apci) m/z=354.1 (M+H).

Intermediate P130

Phenyl(5,5-dioxido-2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-yl)carbamateStep A: Preparation of2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-amine

A suspension of 4-oxotetrahydrothiophene-3-carbonitrile (1.00 g, 7.86mmol) and phenylhydrazine hydrochloride (1.25 g, 8.65 mmol) in absoluteEtOH (40 mL) was refluxed for 2 hours. After removal of solvent underreduced pressure, the white solid residue was triturated with 1 N NaOH(40 mL). The solid was collected by filtration, washed with 0.1 N NaOH,water, and hexanes (approx. 10 mL each) then dried on high vacuum toyield the product as white solid (1.6 g, 95% yield). MS (apci pos)m/z=218.1 (M+H).

Step B: Preparation of phenyl2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-ylcarbamate

To a suspension of 2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-amine(500 mg, 2.30 mmol) in EtOAc (10 mL) was added NaOH (2M aq, 2.3 mL, 4.60mmol), followed by dropwise addition of phenyl carbonochloridate (0.400mL, 3.22 mmol). After stirring at ambient temperature for 2 hours,another portion of phenyl carbonochloridate (0.16 mL, 1.3 mmol) wasadded dropwise, and the reaction was stirred at ambient temperature for15 hours. The reaction mixture was diluted with EtOAc (20 mL) andphase-separated. The organic phase was washed with H₂O, brine (25 mLeach), then dried with Na₂SO₄, filtered and concentrated. The crudematerial was purified by reverse-phase column chromatography, elutingwith 5-70% acetonitrile/water to yield the product as white solid (0.5g, 64% yield). MS (apci pos) m/z=338.1 (M+H).

Step C: Preparation of phenyl(5,5-dioxido-2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-yl)carbamate

To a turbid solution of phenyl2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-ylcarbamate (50 mg, 0.15mmol) in DCM (1.5 mL) at 0° C. was added MCPBA (91 mg, 0.37 mmol, 70-75%water complex), and the mixture was stirred at ambient temperature for10 min. The mixture was then diluted with DCM (3 mL) and washed withsaturated aqueous NaHCO₃ (3×2 mL) and saturated aqueous Na₂S₂O₃ (3×2mL). The organic layer was dried with MgSO₄, filtered and concentratedunder reduced pressure to yield the title product as light yellowishfoamy solid (31 mg, 57% yield, 95% pure). MS (apci pos) m/z=371.0 (M+H).

Intermediate P132

1-methyl-3-(pyrazin-2-yl)-1H-pyrazol-5-amine Step A: Preparation of3-oxo-3-(pyrazin-2-yl)propanenitrile

To a suspension of NaH (60% in mineral oil, 81.1 mg, 2.03 mmol) indioxane (15 mL) was added acetonitrile (0.114 mL, 2.17 mmol), followedby methyl pyrazine-2-carboxylate (200 mg, 1.45 mmol) and the reactionheated to reflux for 2.5 hours. The reaction mixture was cooled toambient temperature and diluted with H₂O (25 mL) and extracted with Et₂O(25 mL). The aqueous phase was neutralized with 2M aqueous HCl (0.7 mL),then extracted with 10% MeOH/DCM (3×25 mL). The combined organic phaseswere washed with brine (25 mL), dried with MgSO₄, filtered, andconcentrated to yield the crude product as an orange syrup (134 mg,62.9% yield). ¹H NMR (CDCl₃) δ 9.32 (d, 1H), 8.87 (d, 1H), 8.68 (dd,1H), 4.34 (s, 2H).

Step B: Preparation of 1-methyl-3-(pyrazin-2-yl)-1H-pyrazol-5-amine

To a suspension of 3-oxo-3-(pyrazin-2-yl)propanenitrile (67.0 mg, 0.455mmol) in EtOH (5 mL) was added methylhydrazine (0.024 mL, 0.455 mmol).The reaction mixture was refluxed for 15 hours, then concentrated invacuo. The crude product was purified by silica column chromatography,eluting with 0-5% MeOH/DCM to yield the product as a brown residue (33mg, 41% yield). MS (apci) m/z=176.2 (M+H).

Intermediate P133

1-methyl-3-(5-methylpyrazin-2-yl)-1H-pyrazol-5-amine

Prepared by the method as described for Intermediate P107, substitutingmethyl isobutyrate in Step A with methyl 5-methylpyrazine-2-carboxylateand propionitrile with acetonitrile to afford3-(5-methylpyrazin-2-yl)-3-oxopropanenitrile. In Step B, phenylhydrazinewas replaced by methylhydrazine to afford the title pyrazole. MS (apci)m/z=190.2 (M+H).

Intermediate P134

1,4-dimethyl-3-(5-methylpyrazin-2-yl)-1H-pyrazol-5-amine

Prepared by the method as described for Intermediate P107, substitutingmethyl isobutyrate in Step A with methyl 5-methylpyrazine-2-carboxylateto afford 2-methyl-3-(5-methylpyrazin-2-yl)-3-oxopropanenitrile. In StepB, phenylhydrazine was replaced by methylhydrazine to afford the titlecompound. MS (apci) m/z=204.1 (M+H).

Intermediate P135

3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-amine Step A: Preparation of5-amino-4-methyl-1-phenyl-1H-pyrazol-3 (2H)-one

A mixture of ethyl 2-cyanopropanoate (5.0 g, 46 mmol) andphenylhydrazine (5.9 g, 46 mmol) in dioxane (10 mL) was heated at 110°C. for 17 hours. The crude material was cooled to ambient temperature,concentrated, and triturated with cold EtOH and Et₂O. The resultantsolid was filtered, washed with Et₂O, and dried under vacuum to give theproduct as a white solid (3.4 g, 39% yield). MS (apci) m/z=190.0 (M−H).

Step B: Preparation of 3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-amine

To a suspension of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one (10.0g, 52.9 mmol) in DMF (100 mL) was added K₂CO₃ (14.6 g, 106 mmol) andbromoethane (4.34 mL, 58.1) at ambient temperature. After stirring for17 hours, the reaction mixture was treated with EtOAc and washed withwater (3×, to obtain the N-alkylation product) and brine, dried withMgSO₄, filtered, and concentrated to give the product (5.35 g, 47%yield). MS (apci) m/z=218.1 (M+H).

The compounds in Table 3 were prepared by the method as described forIntermediate P135, substituting bromoethane with the appropriate alkylhalide or alkyl methanesulfonate.

TABLE 3 Intermediate # Structure Data P200

MS (apci) m/z = 248.1 (M + H) P201

MS (apci) m/z = 204.1 (M + H) P202

MS (apci) m/z = 229.0 (M + H) P203

MS (apci) m/z = 348.1 (M + H) P204

MS (apci) m/z = 310.0 (M + H) P205

MS (apci) m/z = 236.1 (M + H) P206

MS (apci) m/z = 264.0 (M + H) P207

MS (apci) m/z = 260.1 (M + H) P208

MS (apci) m/z = 274.1 (M + H) P209

MS (apci) m/z = 304.1 (M + H) P210

MS (apci) m/z = 262.1 (M + H) P211

MS (apci) m/z = 362.0 (M + H) P212

MS (apci) m/z = 304.1 (M + H)

Intermediate P136

3-(benzyloxy)-1-methyl-1H-pyrazol-5-amine Step A: Preparation of5-amino-1-methyl-4-phenyl-1H-pyrazol-3(2H)-one

To a suspension of ethyl 2-cyano-2-phenylacetate (2.56 g, 13.3 mmol) inEtOH (10 mL) was added dropwise methylhydrazine (1.09 mL, 19.9 mmol).The reaction was heated at 85° C. for 15 hours. The reaction mixture wascooled to 0° C. and filtered. The resultant solid was washed with coldEtOH (20 mL) and Et₂O (20 mL) to give the desired product (2.10 g, 83.7%yield). MS (apci) m/z=190.2 (M+H)

Step B: Preparation of 3-(benzyloxy)-1-methyl-1H-pyrazol-5-amine

A suspension of 5-amino-1-methyl-1H-pyrazol-3(2H)-one (0.35 g, 3.1mmol), Benzyl chloride (0.43 g, 3.4 mmol), and K₂CO₃ (1.3 g, 9.3 mmol)in DMF (4 mL) was heated at 70° C. for 17 hours. After cooling, thereaction mixture was treated with EtOAc, washed with water and brine,dried with MgSO₄, and concentrated in vacuo. The crude product waspurified by silica column chromatography eluting with 2-6% MeOH/DCM toafford the title compound (0.16 g, 25% yield). MS (apci) m/z=204.0(M+H).

Intermediate P137

3-methoxy-1-methyl-4-phenyl-1H-pyrazol-5-amine

To a suspension of 5-amino-1-methyl-4-phenyl-1H-pyrazol-3(2H)-one (StepA of the preparation of Intermediate P136; 208 mg, 1.10 mmol) and K₂CO₃(456 mg, 3.30 mmol) in DMF (5 mL) was added dropwise iodomethane (172mg, 1.21 mmol). The reaction mixture was stirred for 15 hours. Thesolvent was removed under reduced pressure and the residue was purifiedby silica column chromatography eluting with 33% EtOAc/Hexanes to givethe title pyrazole (66.0 mg, 30.4% yield). MS (apci) m/z=204.1 (M+H).

Intermediate P138

3-ethoxy-1-methyl-4-phenyl-1H-pyrazol-5-amine

Prepared as described in Intermediate P137, replacing iodomethane withiodoethane in Step B to afford the title compound. MS (apci) m/z=218.2(M+H).

Intermediate P139

3-ethoxy-1-phenyl-1H-pyrazol-5-amine

Prepared according to the procedure described for Intermediate 135,substituting ethyl-2-cyanopropanoate with ethyl-2-cyanoacetate in StepA. MS (apci) m/z=204.0 (M+H).

The compounds in the following Table were prepared by the method asdescribed for Intermediate P135, substituting bromoethane with theappropriate alkyl halide, alkyl methanesulfonate or epoxide.

Intermediate # Structure MS (apci) m/z P140

286.1 (M + H) P141

303.1 (M + H) P142

262.1 (M + H) P143

402.2 (M + H) P144

276.1 (M + H) P145

363.1 (M + H) P146

248.1 (M + H) P147

248.1 (M + H) P148

302.1 (M + H) P149

302.1 (M + H) P150

262.1 (M + H)

Intermediate 151

1′-(2-methoxyethyl)-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-amine Step A:Preparation of methyl 1-methyl-1H-1,2,4-triazole-3-carboxylate

To a stirred suspension of NaH (60% oil dispersion, 0.346 g, 8.66 mmol)in DMF (20 mL) was added dropwise a solution of methyl1H-1,2,4-triazole-3-carboxylate (1.00 g, 7.87 mmol) in DMF (20 mL) at 0°C. under nitrogen. The reaction mixture was stirred at 0° C. for 1 hour.MeI (0.982 mL, 15.7 mmol) was added dropwise. The reaction mixture wasstirred at ambient temperature overnight. The reaction was poured intocold water and extracted with EtOAc. The combined organic layers werewashed with brine, dried and concentrated. The residue was purified bycolumn chromatography (3:1 hexanes/EtOAc) to give the title compound(0.380 g, 34% yield) as a white solid. MS (apci) m/z=142.1 (M+H).

Step B: Preparation of 1′-(2-methoxyethyl)-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-amine

Prepared according to the method described for Intermediate P109, usingmethyl 1-methyl-1H-1,2,4-triazole-3-carboxylate as a replacement formethyl 2-methoxyacetate, and substituting propionitrile for acetonitrilein Step A. MS (apci) m/z=255.1 (M+H).

Intermediate 152

1′-(2-methoxyethyl)-4-methyl-1-phenyl-1H, 1′H-r[3,4′-bipyrazol]-5-amine

Prepared according to the method described for Intermediate P109, usingethyl 1-(2-methoxyethyl)-1H-pyrazole-4-carboxylate as a replacement formethyl 2-methoxyacetate, and substituting propionitrile for acetonitrilein Step A.

Intermediate 153

5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carbonitrile

To a stirred solution of aniline (2.02 g, 21.7 mmol) in 6 N HCl (22 mL)was added dropwise a solution of NaNO₂ (1.50 g, 21.7 mmol) in water (20mL) at 0-5° C. The reaction mixture was stirred at 0° C. for 15 minutes.Acetic acid (10 mL) was added. This solution was added dropwise to astirred solution of ethyl 2,3-dicyanobutanoate (Prepared according tothe procedure described in Bioorganic & Medicinal Chemistry, 2004, 12,3345-3356, 3.60 g, 21.7 mmol) in acetic acid (12 mL) and water (18 mL)at 0° C. After stirring for 1 hour, concentrated ammonium hydroxide (50mL) was added dropwise followed by THF (50 mL). The reaction was stirredat ambient temperature overnight. The organic layer was separated. Theaqueous layer was extracted with EtOAc. The combined organic layers werewashed with brine, dried and concentrated. The residue was purified byflash chromatography on silica gel (3:1 hexanes/EtOAc) to give the titlecompound (2.95 g, 69% yield). MS (apci) m/z=198.9 (M+H).

Intermediate 155

4-methyl-3-(2-methyl-2H-1,2,3-triazol-4-yl)-1-phenyl-1H-pyrazol-5-amineStep A: Preparation of ethyl 2-methyl-2H-1,2,3-triazole-4-carboxylate

A mixture of ethyl 2H-1,2,3-triazole-4-carboxylate (2.00 g, 14.2 mmol),K₂CO₃ (3.53 g, 25.5 mmol) and methyl iodide (3.54 mL, 56.7 mmol) inacetonitrile (40 mL) was stirred at 50° C. under nitrogen overnight.After cooling to ambient temperature, the mixture was filtered throughCelite®. The filtrate was concentrated in vacuo. The residue waspurified by flash chromatography on silica gel (4:1 hexane/EtOAc) togive the title compound (0.780 g, 35% yield). MS (apci) m/z=156.0 (M+H).

Step B: Preparation of4-methyl-3-(2-methyl-2H-1,2,3-triazol-4-yl)-1-phenyl-1H-pyrazol-5-amine

Prepared according to the method described for Intermediate P109 usingethyl 2-methyl-2H-1,2,3-triazole-4-carboxylate as a replacement formethyl 2-methoxyacetate, and substituting propionitrile for acetonitrilein Step A. MS (apci) m/z=254.9 (M+H).

Intermediate 156

3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-amine

To a stirred solution of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one(Intermediate P135, Step A, 1.00 g, 5.29 mmol) in MeCN (20 mL) was addedPOBr₃ (2.27 g, 7.93 mmol). The reaction mixture was heated at reflux for3 hours. The reaction was concentrate in vacuo. The residue was taken upin DCM. Saturated aqueous NaHCO₃ solution was carefully added. Theaqueous layer was extracted with DCM. The combined organic layers werewashed with brine, dried and concentrated. The residue was purified byflash chromatography on silica gel (1:2 hexane/EtOAc to give the titlecompound (0.23 g, 17% yield). MS (apci) m/z=251.8 (M+H).

Intermediate 157

3-amino-5-methyl-2-phenyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(2H)-oneStep A: Preparation of ethyl5-amino-4-((methylamino)methyl)-1-phenyl-1H-pyrazole-3-carboxylate

To a stirred solution of ethyl5-amino-4-formyl-1-phenyl-1H-pyrazole-3-carboxylate (Prepared accordingto the procedure described in J. Heterocyclic Chemistry, 2010, 47, p.287-291, 142 mg, 0.548 mmol) in DCM (3 mL) was added 2.0 M MeNH₂ in THF(0.822 mL, 1.64 mmol). Two drops of acetic acid was added. The reactionmixture was stirred at ambient temperature overnight. MeOH (0.4 mL) wasadded followed by NaBH₄ (31 mg, 0.82 mmol) portionwise. The reaction wasquenched by the slow addition of water. The mixture was extracted withDCM. The combined organic layers were washed with brine, dried andconcentrated. The crude was used in the next step without furtherpurification. MS (apci) m/z=275.0 (M+H).

Step B: Preparation of3-amino-5-methyl-2-phenyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(2H)-one

To a stirred solution of ethyl5-amino-4-((methylamino)methyl)-1-phenyl-1H-pyrazole-3-carboxylate(crude, 65 mg, 0.24 mmol) in MeOH (0.5 mL) and THF (0.5 mL) was added 2N NaOH (0.24 mL, 0.47 mmol). The reaction mixture was stirred at ambienttemperature for 4 hours and then concentrated in vacuo. To the residuewas added water. The pH was adjusted to 4-5 using 1 N HCl. Water wasevaporated under reduced pressure. The crude acid (58 mg) was dissolvedin DMF (3 mL). Et₃N (66 μL, 0.47 mmol) was added followed by EDCI (90mg, 0.47 mmol) and HOBt (32 mg, 0.24 mmol). The reaction mixture wasstirred at ambient temperature overnight and then partitioned betweenEtOAc and water. The aqueous layer was extracted with EtOAc. Thecombined organic layers were washed with water and brine, dried andconcentrated. The residue was purified by flash chromatography on silicagel (2% MeOH in DCM) to give the title compound (15 mg, 28%) as a whitesolid. MS (apci) m/z=228.9 (M+H).

Intermediate 158

3-methyl-4-(methylthio)-1-phenyl-1H-pyrazol-5-amine

Prepared according to the method described for Intermediate P109,replacing methyl 2-methoxyacetate with ethyl acetate and replacingacetonitrile with 2-(methylthio)acetonitrile in Step A to afford theproduct as a brown oil. MS (apci) m/z=220.1 (M+H).

Intermediate 159

2-(5-amino-4-methyl-l-phenyl-1H-pyrazol-3-yl)-2,2-difluoroethanol

Prepared according to the method described for Intermediate Pill,replacing acetonitrile with propionitrile and replacing methyl3-hydroxy-2,2-dimethylpropanoate with ethyl2,2-difluoro-3-hydroxypropanoate to afford the product as a pale yellowsolid. MS (apci) m/z=254.1 (M+H).

Intermediate 160

2-(5-amino-1-phenyl-1H-pyrazol-3-yl)-2,2-difluoroethanol

Prepared according to the method described for Intermediate Pill,replacing methyl 3-hydroxy-2,2-dimethylpropanoate with ethyl2,2-difluoro-3-hydroxypropanoate to afford the product as a pale yellowsolid. MS (apci) m/z=240.0 (M+H).

Intermediate 161

2-(5-amino-1-phenyl-1H-pyrazol-3-yl)ethanol

Prepared according to the method described in Intermediate Pill,replacing methyl 3-hydroxy-2,2-dimethylpropanoate with methyl3-hydroxypropanoate in Step A. MS (apci) m/z=204.1 (M+H).

Intermediate 162

1-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-2-methylpropan-2-ol StepA: Preparation of ethyl 3-hydroxy-3-methylbutanoate

To a solution of lithium bis(trimethylsilyl)amide (1M in THF) (100 mL,100 mmol) in THF (100 mL) under N₂ and cooled to −78° C. was added ethylacetate (9.74 mL, 100 mmol). The reaction mixture was stirred for 30minutes, and then acetone (8.81 mL, 120 mmol) was added. The reactionmixture was stirred for 10 minutes, and then quenched with HCl (2Maqueous, 70 mL, 140 mmol) and allowed to warm to ambient temperature.The reaction mixture was extracted with EtOAc (2×150 mL). The organicphases were combined and washed with saturated aqueous NaHCO₃ (2×50 mL),dried (MgSO₄), filtered and concentrated to afford the product as ayellow oil (12.8 g, 88% yield). ¹H NMR (CDCl₃) δ 4.18 (q, 3H), 2.49 (s,2H), 1.29 (m, 9H).

Step B: Preparation of 5-hydroxy-5-methyl-3-oxohexanenitrile

To a solution of propionitrile (1.77 mL, 30.5 mmol) in THF (100 mL)under N₂ at −78° C. was added lithium bis(trimethylsilyl)amide (1M inTHF) (27.9 mL, 27.9 mmol). Stirred 1 hour, then ethyl3-hydroxy-3-methylbutanoate (1.86 g, 12.7 mmol) was added. The reactionmixture was stirred at −78° C. for 1 hour, then stirred at 0° C. for 1.5hours, then diluted with H₂O (100 mL) and extracted with Et₂O (50 mL).The phases were separated and the basic aqueous phase was neutralizedwith HCl (6M aqueous, 4.5 mL), then extracted with Et₂O (3×75 mL). Thecombined organic phases were washed with brine (75 mL), dried (MgSO₄),filtered, and concentrated to afford the product as a pale yellow oil(1.24 g, 63% yield). ¹H NMR (CDCl₃) δ 3.54 (m, 1H), 2.89 (s, 2H), 1.50(d, 3H), 1.32 (s, 3H), 1.31 (s, 3H).

Step C: Preparation of1-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-2-methylpropan-2-ol

To a suspension of phenylhydrazine (0.793 mL, 7.99 mmol) and HCl (5-6Min iPrOH, 1.60 mL, 7.99 mmol) in EtOH (25 mL) was added a solution of5-hydroxy-2,5-dimethyl-3-oxohexanenitrile (1.24 g, 7.99 mmol) in EtOH(25 mL). The reaction mixture was refluxed for 17 hours, then cooled toambient temperature, diluted with saturated aqueous NaHCO₃ (10 mL),extracted 10:90 MeOH/DCM (3×25 mL), and the combined organic phases weredried (MgSO₄), filtered and concentrated. Purified by silica columnchromatography eluting with 0-75% acetone/hexanes to afford the titlecompound as an orange oil (1.13 g, 58% yield). MS (apci) m/z=246.1(M+H).

The following pyrazole intermediates were prepared according to themethod used for the preparation of Intermediate 162, Steps B and C,using the appropriate starting material. For the preparation ofIntermediates 168 and 169, the starting material (purchased fromOakwood) was a mixture of cis and trans diastereomers.

Intermediate MS (apci) # Structure Name m/z 163

1-(5-amino-1-phenyl- 1H-pyrazol-3-yl)-2- methylpropan-2-ol 232.1 (M + H)164

(S)-1-(5-amino-4- methyl-1-phenyl- 1H-pyrazol-3-yl)- propan-2-ol 232.1(M + H) 165

(S)-1-(5-amino-1- phenyl-1H-pyrazol- 3-yl)propan-2-ol 218.1 (M + H) 166

(R)-1-(5-amino- 4-methyl-1-phenyl- 1H-pyrazol-3-yl)- propan-2-ol 232.1(M + H) 167

(R)-1-(5-amino-1- phenyl-1H-pyrazol- 3-yl)propan-2-ol 218.1 (M + H) 168

3-(5-amino-4- methyl-1-phenyl- 1H-pyrazol-3-yl)- cyclobutanol 244.1 (M +H) 169

3-(5-amino-1-phenyl- 1H-pyrazol-3-yl)- cyclobutanol 230.1 (M + H)

Intermediate 170

ethyl 5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylate

Prepared according to the method described for Intermediate P109,replacing methyl 2-methoxyacetate with diethyl oxalate and replacingacetonitrile with propionitrile in Step A to afford the product as ayellow solid. MS (apci) m/z=246.1 (M+H).

Intermediate 171

5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid

To a solution of ethyl5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylate (Intermediate 170,1.52 mg, 6.21 mmol) in THF (12 mL) and MeOH (6 mL) was added LiOH (2Maq, 9.31 mL, 18.6 mmol). The reaction mixture was stirred at ambienttemperature for 19 hours, then partially concentrated under reducedpressure, then neutralized with 6M HCl (3.2 mL), extracted with 10:90MeOH/DCM (3×25 mL), and the combined organic extracts were washed withbrine (50 mL), dried (MgSO₄), filtered and concentrated to give thetitle compound as a yellow solid (1.3 g, 96% yield) MS (apci) m/z=218.1(M+H).

Intermediate 172

5-amino-N,4-dimethyl-1-phenyl-1H-pyrazole-3-carboxamide

To a solution of 5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid(Intermediate 171, 223 mg, 1.02 mmol) in acetonitrile (10 mL) were addedDIEA (0.71 mL, 4.10 mmol), methanamine hydrochloride (138 mg, 2.05mmol), DMF (2 mL), and then HATU (428 mg, 1.13 mmol). The reactionmixture was stirred at ambient temperature for 19 hours and thenpartially concentrated under reduced pressure. The mixture was purifiedby reverse-phase column chromatography, eluting with 5-60%acetonitrile/water to afford the title compound as a pale yellow solid(182 mg, 77% yield). MS (apci) m/z=231.1 (M+H).

Intermediate 173

5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxamide

A solution of 5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carbonitrile (150mg, 0.757 mmol) in concentrated H₂SO₄ (0.5 mL) was stirred at ambienttemperature for 17 hours. The reaction mixture was cooled andneutralized by the addition of aqueous NaOH (2M, 11 mL), then extracted10% MeOH/DCM (5×10 mL), and the combined organic extracts were washedwith brine, dried (MgSO₄), filtered and concentrated under reducedpressure to afford the title compound as a white solid (151 mg, 95%yield). MS (apci) m/z=239.1 (M+Na).

Intermediate 174

ethyl 5-amino-3-ethoxy-1-phenyl-1H-pyrazole-4-carboxylate Step A:Preparation of diethyl 2-cyanomalonate

To a suspension of NaH (60 wt % in mineral oil, 499 mg, 12.49 mmol) inTHF (100 mL) under N₂ at 0° C. was added diethyl malonate (1.90 mL,12.49 mmol). The ice bath was removed and the reaction mixture wasstirred at ambient temperature for 30 minutes, then cooled to 0° C. andcyanic bromide (5M in MeCN, 2.5 mL, 12.49 mmol) was added. The reactionmixture was stirred at ambient temperature for 19 hours, then dilutedwith H₂O (50 mL), extracted with Et₂O (50 mL). The aqueous phase wasneutralized with HCl (2M aq, 3 mL) then extracted with DCM (2×50 mL).The combined DCM extracts were dried (MgSO₄), filtered, and concentratedto afford the product as a yellow oil (837 mg, 36% yield). 1H NMR(CDCl₃) δ 4.46 (s, 1H), 4.35 (q, 4H), 1.35 (t, 6H).

Step B: Preparation of ethyl5-amino-3-ethoxy-1-phenyl-1H-pyrazole-4-carboxylate

Prepared according to the method described for Intermediate P135,replacing ethyl 2-cyanopropanoate with diethyl 2-cyanomalonate in Step Ato afford the product as a brown syrup (400 mg, 32% yield). MS (apci)m/z=276.1 (M+H).

Intermediate 175

4-methyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-1-phenyl-1H-pyrazol-5-amineStep A: Preparation ofN′-acetyl-5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carbohydrazide

To a solution of 5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid(Intermediate 171, 93 mg, 0.428 mmol) in DCM (5 mL) and DIEA (0.149 mL,0.856 mmol) was added isobutyl carbonochloridate (0.061 mL, 0.471 mmol).The reaction mixture was stirred at ambient temperature for 1 hour, thenacetohydrazide (48 mg, 0.642 mmol) was added. The reaction mixture wasstirred at ambient temperature for 18 hours, then diluted with H₂O (10mL), extracted DCM (2×10 mL), dried (MgSO₄), filtered and concentratedunder reduced pressure to afford the product as a pale yellow solid (119mg, 101% yield). MS (apci) m/z=274.1 (M+H).

Step B: Preparation of4-methyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-1-phenyl-1H-pyrazol-5-amine

A mixture ofN′-acetyl-5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carbohydrazide (117mg, 0.428 mmol) and POCl₃ (0.5 mL) was heated in a pressure tube to 90°C. for 1 hour. The reaction mixture was transferred to a separatoryfunnel with EtOAc (5 mL), then diluted with saturated aqueous NaHCO₃ (20mL), extracted with EtOAc (2×15 mL), dried (MgSO₄), filtered andconcentrated. The residue was purified by silica column chromatographyeluting with 0-75% acetone/hexanes to afford the title compound as ayellow solid (19.6 mg, 18% yield). MS (apci) m/z=256.1 (M+H).

Intermediate 176

4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1-phenyl-1H-pyrazol-5-amine

To a suspension of NaH (60% in mineral oil, 36 mg, 0.897 mmol) in THF (5mL) under N₂ was added N-hydroxyacetimidamide (66 mg, 0.897 mmol). Thereaction mixture was heated to reflux for 1 hour, then cooled to ambienttemperature and ethyl5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylate (Intermediate 170,200 mg, 0.815 mmol) was added. The reaction mixture was heated to refluxfor 18 hours, then cooled to ambient temperature and additional NaH (60%in mineral oil, 18 mg, 0.449 mmol) was added. The reaction mixture washeated to reflux for 4 hours, then diluted with H₂O (10 mL), extractedDCM (2×15 mL), and the combined organic extracts were dried (MgSO₄),filtered and concentrated under reduced pressure. The residue waspurified by silica column chromatography eluting with 0-50%acetone/hexanes to afford the title compound as an orange solid (84 mg,40% yield). MS (apci) m/z=256.1 (M+H).

Intermediate 177

3-(3-methyl-1,2,4-oxadiazol-5-yl)-1-phenyl-1H-pyrazol-5-amine

Prepared according to the method described in Intermediate 176,replacing ethyl 5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylate withethyl 5-amino-1-phenyl-1H-pyrazole-3-carboxylate (Nanjing ChemlinChemical Co.) to afford the product as a tan solid (83 mg, 53% yield).MS (apci) m/z=242.1 (M+H).

Intermediate 178

4-methyl-1-phenyl-3-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-5-amineStep A: Preparation of 2,2,2-trifluoro-N′-hydroxyacetimidamide

To a suspension of hydroxylamine hydrochloride (5.45 g, 78.4 mmol) inMeOH (100 mL) was added NaOMe (25 wt % solution in MeOH, 17.9 mL, 78.4mmol) and the mixture stirred at ambient temperature for 10 minutes,then filtered and the solid was washed with MeOH. The filtrate wascooled to 0° C. and then 2,2,2-trifluoroacetonitrile (7.45 g, 78.4 mmol)gas was bubbled into the solution over 30 minutes. The reaction mixturewas then allowed to warm to ambient temperature for 19 hours. Thesolution was concentrated under reduced pressure to 50 mL and the solidswere filtered. The filtrate was concentrated, re-suspended in cold MeOH,and filtered. The filtrate was concentrated, again re-suspended in coldMeOH, and filtered. The filtrate was concentrated to give the product asa waxy white solid (6.7 g, 67% yield). ¹H NMR (CD₃CN) δ 8.32 (s, 1H),5.25 (br s, 2H). ¹⁹F NMR (CD₃CN) 6-71.8 (s).

Step B: Preparation of4-methyl-1-phenyl-3-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-5-amine

To a suspension of NaH (60% in mineral oil, 356 mg, 0.897 mmol) in THF(5 mL, 0.815 mmol) under N₂ was added2,2,2-trifluoro-N′-hydroxyacetimidamide (115 mg, 0.897 mmol). Thereaction mixture was heated to reflux for 1 hour, then cooled to ambienttemperature and powdered 4 A molecular sieves (200 mg) and ethyl5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylate (Intermediate 170;200 mg, 0.815 mmol) were added and heated to reflux. The reactionmixture was heated to reflux for 18 hours, then filtered, diluted withH₂O (15 mL), extracted DCM (2×25 mL), and the combined organic extractswere washed with brine (25 mL), dried (MgSO₄), filtered and concentratedunder reduced pressure. The residue was purified by silica columnchromatography eluting with 0-50% acetone/hexanes to afford the titlecompound as a white solid (44 mg, 17% yield). MS (apci) m/z=310.1 (M+H).

Intermediate 179

2-phenyl-2H-indazol-3-amine Step A: Preparation of1-(2-iodophenyl)-2-phenyldiazene

To a solution of 2-iodoaniline (1.00 g, 4.57 mmol) in acetic acid (46mL) was added nitrosobenzene (0.880 g, 8.22 mmol) and the mixture washeated at 85° C. for 16 hours. The mixture was cooled to ambienttemperature, poured into water and slowly treated with saturated NaHCO₃until basic. The mixture was extracted with EtOAc (3×) and the combinedextracts were washed with water, saturated NaCl and dried over MgSO₄.The solution was filtered, concentrated and the residue purified byreverse phase chromatography to provide the title compound as a redsolid (0.880 g, 63% yield). ¹H NMR (CDCl₃) δ 7.23-7.39 (m, 3H), 7.64 (d,1H), 7.56-7.51 (m, 3H), 7.45 (t, 1H), 7.1 (t, 1H).

Step B: 2-(phenyldiazenyl)benzonitrile

To a solution of 1-(2-iodophenyl)-2-phenyldiazene (0.44 g, 1.4 mmol) in1-propanol (14 mL) was added CuCN (0.900 g, 10.0 mmol) and the reactionwas heated at reflux for 16 hours. The mixture was cooled to ambienttemperature, filtered and the collected solid washed with CH₂Cl₂. Thecombined filtrate and washes were concentrated to provide the titlecompound as red-orange solid that was dried in vacuum (0.280 g, 95%yield). ¹H NMR (CDCl₃) δ 8.03-8.06 (m, 2H), 7.88 (dd, 2H), 7.71 (t, 1H),7.54-7.58 (m, 4H).

Step C: 2-phenyl-2H-indazol-3-amine

A mixture of 2-(phenyldiazenyl)benzonitrile (0.28 g, 1.35 mmol) andSnCl₂ dihydrate (0.562 mL, 6.76 mmol) in EtOH (14 mL) was heated atreflux for 16 hours. The mixture was cooled to ambient temperature andconcentrated. The residue was diluted with EtOAc and water and filtered.The aqueous layer was removed and the EtOAc layer was washed with water.The combined aqueous fractions were basified with saturated NaHCO₃ andextracted with CH₂Cl₂ (2×). The combined organic layers were dried overMgSO₄, filtered and concentrated to provide the title compound as alight purple solid that was dried in vacuum (0.241 g, 85% yield). ¹H NMR(CDCl₃) δ 7.69 (d, 2H), 7.52-7.58 (m, 3H), 7.47 (d, 2H), 7.26 (t, 1H),6.90 (t, 1H), 4.28 (br s, 2H).

Intermediate 180

3-ethoxy-4-methyl-1-(pyrazin-2-yl)-1H-pyrazol-5-amine Step A:5-amino-4-methyl-1-(pyrazin-2-yl)-1H-pyrazol-3 (2H)-one

To a mixture of 2-hydrazinylpyrazine (0.551 g, 5.00 mmol) and ethyl2-cyanopropanoate (0.669 g, 5.00 mmol) in abs. EtOH (10 mL) was added 3MNaOEt in EtOH (0.167 mL, 0.501 mmol) and the mixture was heated atreflux for 64 hours. The mixture was concentrated and the residualyellow-brown solid was treated with EtOAc (30 mL) and sonicated. Theresulting tan suspension was stirred vigorously for 8 hours. The solidwas collected via vacuum filtration, washed with EtOAc and dried invacuum to afford the title compound as a light tan powder (682 mg, 71%).¹H NMR (DMSO d₆) δ 10.3 (br s, 1H), 8.82 (s, 1H), 8.30 (d, 2H), 6.55 (s,2H), 1.71 (s, 3H).

Step B: 3-ethoxy-4-methyl-1-(pyrazin-2-yl)-1H-pyrazol-5-amine

A mixture of 5-amino-4-methyl-1-(pyrazin-2-yl)-1H-pyrazol-3(2H)-one (382mg, 2.00 mmol) and powdered K₂CO₃ (552 mg, 4.00 mmol) in dry DMF (3.0mL) was stirred at ambient temperature for 10 minutes. The mixture wascooled to 0° C. and bromoethane (229 mg, 2.10 mmol) was added. Themixture was allowed to reach ambient temperature and was stirred 24hours. The reaction mixture poured into cold H₂O (12 mL), allowed toreach ambient temperature and was extracted with EtOAc (3×). Thecombined extracts were washed with saturated NaCl (2×), dried over MgSO₄and activated carbon. The dried solution was diluted with and equalvolume of hexanes and filtered through a SiO₂ plug capped with a MgSO₄layer eluting with 50% EtOAc-hexanes. The filtrate was concentrated andthe residual yellow solid was washed with hexanes (3×) and dried invacuum to afford the title compound as a light yellow crystalline solid(195 mg, 45%). ¹H NMR (CDCl₃) δ 9.10 (s, 1H), 8.23 (s, 1H), 8.14 (s,1H), 5.50 (br s, 2H), 4.33 (q, 2H), 1.80 (s, 3H), 1.42 (t, 3H).

Intermediate 181

2-(pyridazin-4-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine

A suspension of 4-hydrazinylpyridazine hydrobromide (0.368 g, 1.93 mmol)in absolute EtOH (5 mL) was treated with 2-oxocyclopentanecarbonitrile(0.191 g, 1.75 mmol) and the mixture was heated at reflux for 22 hours.The mixture was cooled to ambient temperature and was concentrated to anorange solid. The solid was suspended in 1M NaOH and stirred for 10minutes. The solid was collected, washed thoroughly with H₂O and Et₂Oand dried in vacuum to furnish title compound as a tan powder (0.323 g,92%). MS (apci) m/z=202.1 (M+H).

Intermediate 182

(5-amino-1-phenyl-1H-pyrazol-3-yl)methanol Step A: Ethyl2-(tert-butyldimethylsilyloxy)acetate

A mixture of ethyl 2-hydroxyacetate (3.00 g, 28.8 mmol), TBDMS-Cl (5.21g, 34.6 mmol) and imidazole (2.55 g, 37.5 mmol) was stirred at ambienttemperature for 60 hours. The mixture was concentrated and the residuewas purified by SiO₂ chromatography eluting with 10% EtOAc-hexanes toprovide the title compound as a colorless oil (4.12 g, 65%). ¹H NMR(CDCl₃) δ 4.12 (s, 2H), 4.09 (q, 2H), 1.17 (t, 3H), 0.18 (s, 9H), 0.00(s, 6H).

Step B: (5-amino-1-phenyl-1H-pyrazol-3-yl)methanol

A solution of acetonitrile (0.526 mL, 10.1 mmol) in dry THF (20.4 mL,9.16 mmol) was cooled to −78° C. and 2.5M nBuLi in hexanes (4.21 mL,10.5 mmol) was added dropwise. The reaction mixture was stirred for 15minutes and ethyl 2-(tert-butyldimethylsilyloxy)acetate (2.00 g, 9.16mmol) was added. The reaction mixture was allowed to warm to ambienttemperature and was stirred for 2 hours. The reaction mixture wasdiluted with ice water and was concentrated. The residual aqueousmixture was acidified to pH=5 and extracted with EtOAc (3×). Thecombined organics were washed with brine, dried over MgSO₄, filtered andconcentrated. The residual brown oil was dissolved in MeOH (23 mL) andphenyl hydrazine (0.907 mL, 9.14 mmol) was added. The mixture wastreated with concentrated HCl (3.81 mL, 45.7 mmol) and heated at refluxfor 18 hours. Upon cooling, the mixture was concentrated and the residuewas partitioned into in H₂O and CH₂Cl₂. The mixture was filtered and theorganic layer was removed from the filtrate. The aqueous portion waswashed with CH₂Cl₂ and was treated with saturated NaHCO₃ until basic.The aqueous mixture was extracted with CH₂Cl₂ (3×) and the combinedorganic fractions were dried over MgSO₄, filtered and concentrated. Theresidue was purified by silica column chromatography using 70-100%EtOAc/hexanes gradient elution followed by 0-5% MeOH/EtOAc. The productpools were combined and concentrated to give the title compound as ayellow foam (0.760 g, 44% yield). MS (apci) m/z=190.1 (M+H).

Intermediate 183

4-methyl-3-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)-1-phenyl-1H-pyrazol-5-amine

The title compound was prepared by the method as described forIntermediate P135, substituting bromoethane with3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride. The productwas isolated as a gold syrup (110 mg, 27%). MS (apci) m/z=285.1 (M+H).

Intermediate 184

5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl dimethylcarbamate

A mixture of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one(Intermediate P135 Step A, 0.378 g, 2.00 mmol) and powdered K₂CO₃ (0.553g, 4.00 mmol) in dry DMF (4 mL) was stirred at ambient temperature for 5minutes. Dimethylcarbamoyl chloride (0.206 mL, 2.20 mmol) was added andthe mixture was stirred for 6 hours. The mixture was poured into chilledH₂O (40 mL) and was extracted with EtOAc (3×). The combined extractswere washed with saturated NaCl (2×), dried over MgSO₄ and filteredthrough a SiO₂ plug capped with a MgSO₄ layer (EtOAc elution). Thefiltrate was concentrated and the residue dried in vacuum to give thetitle compound as a light gold syrup (0.507 g, 97%). MS (apci) m/z=261.1(M+H).

Intermediate 185

5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl morpholine-4-carboxylate

The title compound was prepared using morpholine-4-carbonyl chloride inthe procedure outlined for 5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yldimethylcarbamate (Intermediate 184). The compound was isolated as alight yellow wax (0.285 g, 47%). ¹H NMR (CDCl₃) δ 7.54 (d, 2H), 7.43 (t,2H), 7.31 (t, 1H), 3.66-3.78 (m, 8H), 3.57 (br s, 2H), 1.85 (s, 3H).

Intermediate 186

(S)-3-(2-((tert-butyldimethylsilyl)oxy)-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-amineStep A:(S)-1-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yloxy)-3-methoxypropan-2-ol

A mixture of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one (P135 StepA, 1.21 g, 6.40 mmol) and powdered K₂CO₃ (1.77 g, 12.8 mmol) in dry DMF(12 mL) was stirred at ambient temperature for 10 minutes.(S)-2-(methoxymethyl)oxirane (0.622 mL, 6.72 mmol) was added and themixture was stirred at 80° C. for 6 hours. The mixture was cooled toambient temperature, poured into chilled H₂O (25 mL) and extracted withEtOAc (3×). The combined extracts were washed with saturated NaCl (2×),dried over MgSO₄ and filtered through a SiO₂ plug capped with a layer ofMgSO₄ eluting with EtOAc. The filtrate was concentrated to give thetitle compound as a colorless, viscous oil (701 mg, 40%). MS (apci)m/z=278.1 (M+H).

Step B:(S)-3-(2-((tert-butyldimethylsilyl)oxy)-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-amine

To a solution of TBDMS-Cl (725 mg, 4.81 mmol) and imidazole (390 mg,5.72 mmol) in dry DMF (7.0 mL) was added(S)-1-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yloxy)-3-methoxypropan-2-ol(635 mg, 2.29 mmol) in dry DMF (2 mL). The mixture stirred at ambienttemperature for 2.5 hours. The mixture added to H₂O (70 mL), mixed for 5minutes and extracted with Et₂O (3×). The combined extracts were washedwith saturated NaCl (2×) and dried over MgSO₄. The dried solution wasfiltered through a SiO₂ plug capped with a layer of MgSO₄ (Et₂Oelution). The filtrate was concentrated to give the title compound as acolorless oil that was dried in vacuum (940 mg, 105%). MS (apci)m/z=392.2 (M+H). ¹H NMR (CDCl₃) δ 7.50 (d, 2H), 7.40 (t, 2H), 7.23 (t,1H), 4.09-4.30 (m, 3H), 3.57 (br s, 2H), 3.38-3.44 (m, 2H), 3.32 (s,3H), 1.83 (s, 3H), 0.88 (s, 9H), 0.11 (s, 6H).

Intermediate 187

(R)-3-(2-((tert-butyldimethylsilyl)oxy)-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-amine

The title compound was prepared using the procedure described for(S)-3-(2-((tert-butyldimethylsilyl)oxy)-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-amine(Intermediate 186) substituting (S)-2-(methoxymethyl)oxirane with(R)-2-(methoxymethyl)oxirane in Step A. The product was obtained as acolorless syrup (921 mg, 38% over 2 steps). MS (apci) m/z=392.2 (M+H).¹H NMR (CDCl₃) δ 7.50 (d, 2H), 7.40 (t, 2H), 7.23 (t, 1H), 4.09-4.30 (m,3H), 3.57 (br s, 2H), 3.38-3.44 (m, 2H), 3.32 (s, 3H), 1.83 (s, 3H),0.88 (s, 9H), 0.11 (s, 6H).

Intermediate 188

tert-butyl4-((5-amino-1-phenyl-1H-pyrazol-3-yl)methoxy)piperidine-1-carboxylateStep A: tert-butyl 4-(2-ethoxy-2-oxoethoxy)piperidine-1-carboxylate

A solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2.00 g, 9.94mmol) in dry THF (25 mL) was cooled to 0° C. and KOtBu (1.12 g, 9.94mmol) was added. The mixture was allowed to reach ambient temperatureand was stirred for 10 minutes. The mixture was cooled to 0° C. andethyl 2-bromoacetate (1.65 mL, 14.9 mmol) was added dropwise. Thereaction was allowed to reach ambient temperature and was stirred for 17hours. The mixture was partitioned into in H₂O and EtOAc, mixed and theorganic layer was removed. The organic layer was dried over MgSO₄,filtered and concentrated. The residual thick yellow oil was purified bysilica chromatography using a 10-25% EtOAc/hexanes gradient elution toafford the title compound as a colorless oil (0.967 g, 34% yield). ¹HNMR (CDCl₃) δ 4.22 (q, 2H), 4.12 (s, 2H), 3.67-3.84 (m, 2H), 3.52-3.63(m, 1H), 3.05-3.11 (m, 2H), 1.81-1.90 (m, 2H), 1.53-1.62 (m, 2H), 1.45(s, 9H), 1.29 (t, 3H).

Step B: tert-butyl4-((5-amino-1-phenyl-1H-pyrazol-3-yl)methoxy)piperidine-1-carboxylate

A solution of diisopropylamine (1.08 mL, 7.74 mmol) in dry THF (5 mL)was cooled to 0° C. and 2.5M nBuLi in hexanes (2.96 mL, 7.41 mmol) wasslowly added. The mixture was stirred at 0° C. for 10 minutes and wascooled to −78° C. Acetonitrile (0.404 mL, 7.74 mmol) was added and themixture was stirred for 15 minutes. A solution of tert-butyl4-(2-ethoxy-2-oxoethoxy)piperidine-1-carboxylate (0.967 g, 3.37 mmol) inTHF (2.5 mL) was added and the mixture was stirred at −78° C. for 1hour. The mixture was allowed to reach ambient temperature, was quenchedwith ice water and concentrated. The residual aqueous mixture wasneutralized with 2M HCl and was extracted with CH₂Cl₂ (3×). The combinedorganic fractions were dried over MgSO₄, filtered and concentrated toprovide the crude cyano-ketone as a yellow oil that was used immediatelyin the next step.

Step C: tert-butyl4-((5-amino-1-phenyl-1H-pyrazol-3-yl)methoxy)piperidine-1-carboxylate

The crude oil obtained in Step B was dissolved in EtOH (17 mL) andphenylhydrazine (0.396 mL, 3.99 mmol) was added. The mixture was heatedat 60° C. for 60 hours, was cooled to ambient temperature and wasconcentrated. The residue was partitioned into EtOAc and water, mixedand the organic layer removed. The aqueous layer was extracted withEtOAc (2×) and the combined EtOAc portions were dried over MgSO₄,filtered and concentrated. The residual orange oil was purified bysilica chromatography using a 10-100% EtOAc/hexanes gradient elution.The pooled product fractions were concentrated and the residualyellow-orange oil was re-purified by reverse phase HPLC using a 0-100%acetonitrile/water gradient to provide the title compound as an orangefoam (0.264 g, 21% yield). MS (apci) m/z=373.2 (M+H).

Intermediate 189

1-phenyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine Step A:3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanenitrile

A 1M solution of LHMDS in dry THF (26.3 mL, 26.3 mmol) was cooled to−78° C. and acetonitrile (1.43 mL, 27.5 mmol) was added dropwise over 2minutes. The mixture was stirred at −78° C. for 1 hour and a solution ofmethyl tetrahydro-2H-pyran-4-carboxylate (3.41 mL, 25.0 mmol) in dry THF(12 mL) was added. The mixture was stirred for 1 hour, the dry ice bathwas removed and the mixture allowed to reach ambient temperature. Themixture was poured into chilled H₂O (250 mL) and was extracted with Et₂O(3×). The aqueous portion was cooled to 0° C. and 6M HCl was addeddropwise to pH=3 (starting pH=12). The mixture was extracted with EtOAc(3×) and the combined extracts were dried over MgSO₄. The solutioneluted through a SiO₂ plug eluting with EtOAc. The filtrate wasconcentrated to give the title compound as a colorless oil (2.52 g,66%). ¹H NMR (CDCl₃) δ 3.99-4.06 (m, 2H), 3.54 (s, 2H), 3.46 (t, 2H),2.76-2.86 (m, 1H), 1.70-1.86 (m, 4H).

Step B: 1-phenyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine

To a solution of 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanenitrile (2.30g, 12.8 mmol) in absolute EtOH (35 mL) was added phenylhydrazinehydrochloride (2.21 g, 15.3 mmol) and the mixture was heated at refluxuntil complete by TLC (5 hours). The mixture was cooled to ambienttemperature and was concentrated. The residue was partitioned in H₂O (75mL) and EtOAc (40 mL). 2M NaOH was added to pH=5 with vigorous mixing,the organic layer was removed and the aqueous was extracted with EtOAc(2×). The combined EtOAc fractions were washed with H₂O and saturatedNaCl. The solution was diluted with an equal volume of hexanes, driedover MgSO₄/activated carbon and eluted through a SiO₂ plug eluting with50% EtOAc-hexanes. The filtrate was concentrated to give a gold syrup.The syrup was treated with Et₂O and stirred until a fine, granularsuspension formed. The solid was collected, washed with Et₂O and driedin vacuum to furnish the title compound as a white solid (2.01 g, 65%).¹H NMR (CDCl₃) δ 7.55 (d, 2H), 7.46 (t, 2H), 7.32 (t, 1H), 5.49 (s, 1H),4.00-4.08 (m, 2H), 3.97 (br s, 2H), 3.52 (dt, 2H), 2.86 (m, 1H)1.73-1.93 (m, 4H).

The following compounds were prepared according to the method used forthe preparation of1-phenyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine (Intermediate189) using either acetonitrile or propiononitrile in Step A inconjunction with the appropriate ester.

Intermediate # Structure Data 190

MS (apci) m/z = 343.1 (M + H) 191

MS (apci) m/z = 258.0 (M + H) 192

¹H NMR (CDCl₃) δ 7.62 (d, 2H), 7.50 (t, 2H), 7.37 (t, 1H), 5.72 (s, 1H),3.91 (br s, 2H), 2.58 (s, 3H), 2.44 (s, 3H). 193

¹H NMR (CDCl₃) δ 7.60 (d, 2H), 7.49 (t, 2H), 7.37 (t, 1H), 6.45 (s, 1H),3.67 (br s, 2H), 2.45 (s, 3H), 2.24 (s, 3H). 194

¹H NMR (CDCl₃) δ 7.45- 7.56 (m, 4H), 7.35 (t, 1H), 4.00-4.06 (m, 2H),3.88 (dt, 2H), 3.62 (br s, 2H), 2.18-2.34 (m, 4H), 2.11 (s, 3H). 195

MS (apci) m/z = 343.2 (M + H) 196

MS (apci) m/z = 343.2 (M + H) 197

MS (apci) m/z = 329.2 (M + H) 198

MS (apci) m/z = 329.2 (M + H)

Intermediate 199

Phenyl 1′,4-dimethyl-1-phenyl-1H, 1′H-3,4′-bipyrazol-5-ylcarbamate StepA: ethyl 1-methyl-1H-pyrazole-4-carboxylate

To a 3000-mL three-necked flask was added ethyl 2-formyl-3-oxopropanoate(100 g, 694 mmol), followed by anhydrous 200-proof EtOH (694 mL) toobtain a clear yellowish solution. The reaction was cooled in an icebath to 5° C., and then methylhydrazine (35.8 mL, 680 mmol) was addeddropwise. A vigorous exotherm was observed during hydrazine addition andthe temperature was kept below 12° C. by controlling the addition rate.After the hydrazine addition was complete, the ice bath was removed, andthe reaction was allowed to stir at ambient temperature overnight. Thereaction was concentrated on a rotary evaporator to a crude orange oil.The crude was taken up in DCM and re-concentrated, then on high vacuumfor 2 days to yield tan orange oil. LC/MS and ¹H NMR showed essentiallypure ethyl 1-methyl-1H-pyrazole-4-carboxylate (106 g, 99.1%).

Step B: 2-methyl-3-(1-methyl-1H-pyrazol-4-yl)-3-oxopropanenitrile

To a four-necked 5-liter round bottomed flask fitted with an overheadstirrer and addition funnel was charged LHMDS (1444 mL, 1444 mmol) (1.0Min THF). The solution was cooled in an acetone/dry ice bath first(internal temperature of −79° C.) under nitrogen, followed by slowaddition of propiononitrile (103 mL, 1444 mmol) via dropping funnel. Themixture was stirred at −80° C. for 90 minutes. A solution of ethyl1-methyl-1H-pyrazole-4-carboxylate (106 g, 688 mmol) in anhydrous THF(500 mL) was then introduced dropwise via an addition funnel (additiontime: about 45 minutes; internal temperature during addition remainedbelow −76° C.). After the addition was complete, the reaction wasallowed to slowly warm to ambient temperature and stirred overnight. Anorange glass deposited on the bottom of the flask. The organics weredecanted and the glass was dissolved in warm water. The mixture waswashed with with ether (3×1000 mL). The aqueous phase was thenpH-adjusted to 5 (pH paper) using concentrated HCl and saturatedbicarbarbonate solution The aqueous layer was extracted with DCM (3×1000mL). The combined organic extracts were dried over MgSO₄ filtered andconcentrated to yield the2-methyl-3-(1-methyl-1H-pyrazol-4-yl)-3-oxopropanenitrile as an amberoil (92 g, 82%). MS (apci) m/z=162.1 (M−H).

Step C: 1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-amine

A 3 L, 3 necked round bottomed flask was charged with2-methyl-3-(1-methyl-1H-pyrazol-4-yl)-3-oxopropanenitrile (60 g, 368mmol) absolute anhydrous ethanol (1000 mL) and phenylhydrazinehydrochloride (58 g, 404 mmol) at ambient temperature to form ayellowish suspension. The reaction vessel was equipped with a watercondenser and refluxed (using a heating mantle) overnight. The reactionwas concentrated and 1M NaOH (1 L) was added and the solid was broken upand collected. The solid was washed with water and hexanes. A secondcrop crashed out in the filtrate and was collected. The combined solidswere crushed and triturated with ether (500 mL). The solid was collectedfiltration, washed with hexanes and air dried under vacuum to provide1′,4-dimethyl-1-phenyl-1H, 1′H-3,4′-bipyrazol-5-amine (93 g, 100%).

Step D: phenyl 1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-ylcarbamate

In a 3 L, round bottomed flask was charged with1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-amine (50 g, 197.4 mmol)and EtOAc (1000 mL) to obtain a clear brownish solution. To this wasadded NaOH (2M aq) (500 mL) in one portion to obtain a turbid mixture(both the aqueous and organic layers were clear but a precipitate wasobserved in between the two layers). After 3 minutes, phenylcarbonochloridate (74.29 mL, 592.2 mmol) was added slowly at ambienttemperature exotherm to 33° C. The reaction stirred at ambienttemperature for 2 hours. Additional phenyl carbonochloridate (10 mL) wasadded. After 30 minutes the organics were separated, washed with brineand concentrated in vacuo. The product was purified by silica gelchromatography (eluting with 75% ethyl acetate in hexanes) to providephenyl 1′,4-dimethyl-1-phenyl-1H, 1′H-3,4′-bipyrazol-5-ylcarbamate (60g, 81.4%).

Intermediate 200

phenyl 1′,4-dimethyl-1-phenyl-1H, 1′H-3,4′-bipyrazol-5-ylcarbamate

A 3 L, round bottomed flask was charged with1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-amine (50 g, 197.4 mmol)and EtOAc (1000 mL) to obtain a clear brownish solution. To this wasadded NaOH (2M aq) (500 mL) in one portion to obtain a turbid mixture(the aqueous and organic layers were clear, but a precipitate wasobserved in between the two layers). After 3 minutes, phenylcarbonochloridate (74.29 mL, 592.2 mmol) was added slowly at ambienttemperature (the temperature of the reaction mixture increased to 33° C.during the addition). The reaction stirred at ambient temperature for 2hours. Additional phenyl carbonochloridate (10 mL) was added. After 30minutes the organics layers were separated, washed with brine andconcentrated in vacuo. The residue was purified by silica gelchromatography (eluting with 75% ethyl acetate in hexanes) to providephenyl 1′,4-dimethyl-1-phenyl-1H, 1′H-3,4′-bipyrazol-5-ylcarbamate (60g, 81.4%).

Intermediate 201

phenyl (4-chloro-3-ethoxy-1-phenyl-1H-pyrazol-5-yl)carbamate Step A:Preparation of phenyl (3-ethoxy-1-phenyl-1H-pyrazol-5-yl)carbamate

To a suspension of 3-ethoxy-1-phenyl-1H-pyrazol-5-amine (IntermediateP139, 169 mg, 0.832 mmol) in EtOAc (5 mL) at 0° C. was added 2.0 Maqueous NaOH solution (1.25 mL, 2.50 mmol), followed by dropwiseaddition of phenyl carbonochloridate (0.178 mL, 1.41 mmol). The reactionwas stirred at ambient temperature for 15 hours. The reaction mixturewas diluted with EtOAc and phase-separated. The organic layer was washedwith water and brine, dried over MgSO₄, and concentrated. The residuewas purified by flash chromatography on silica gel (6:1 hexanes:EtOAc)to give the title compound (219 mg, 81% yield). MS (apci) m/z=324.1(M+H).

Step B: Preparation of phenyl(4-chloro-3-ethoxy-1-phenyl-1H-pyrazol-5-yl)carbamate

To a solution of phenyl 3-ethoxy-1-phenyl-1H-pyrazol-5-ylcarbamate (92mg, 0.28 mmol) and pyridinium 4-methylbenzenesulfonate (7.2 mg, 0.028mmol) in DCM (2 mL) was added N-chlorosuccinimide (42 mg, 0.31 mmol) atambient temperature. The mixture was stirred at ambient temperature for2 days and then concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel (9:1, hexanes/EtOAc) togive the title compound (76 mg, 75% yield). MS (apci) m/z=358.1 (M+H).

Intermediate 203

Phenyl(4-bromo-3-(2-hydroxy-2-methylpropoxy)-1-phenyl-1H-pyrazol-5-yl)carbamateStep A: Preparation of 5-amino-1-phenyl-1H-pyrazol-3(2H)-one

Prepared according to the method described for Intermediate P1,replacing 4,4-dimethyl-3-oxopentanenitrile with ethyl 2-cyanoacetate,and substituting phenylhydrazine for ethyl 3-hydrazinylbenzoatehydrochloride. MS (apci) m/z=176.0 (M+H).

Step B: Preparation of1-((5-amino-1-phenyl-1H-pyrazol-3-yl)oxy)-2-methylpropan-2-ol

A mixture of 5-amino-1-phenyl-1H-pyrazol-3(2H)-one (0.330 g, 1.88 mmol),2,2-dimethyloxirane (0.143 g, 1.98 mmol) and K₂CO₃ (0.521 g, 3.77 mmol)in DMA (5 mL) was heated at 80° C. for 3 days. After cooling, thereaction mixture was diluted with EtOAc, washed with water and brine anddried over MgSO₄. The mixture was filtered through a pad of SiO₂ elutingwith EtOAc to yield the title compound. MS (apci) m/z=248.1 (M+H).

Step C: Preparation of phenyl(3-(2-hydroxy-2-methylpropoxy)-1-phenyl-1H-pyrazol-5-yl)carbamate

Prepared according to the method described for Intermediate 201. Step Ausing 1-((5-amino-1-phenyl-1H-pyrazol-3-yl)oxy)-2-methylpropan-2-ol as areplacement for 3-ethoxy-1-phenyl-1H-pyrazol-5-amine. MS (apci)m/z=368.1 (M+H).

Step D: Preparation of phenyl(4-bromo-3-(2-hydroxy-2-methylpropoxy)-1-phenyl-1H-pyrazol-5-yl)carbamate

Prepared according to the method described for Intermediate 201, Step Busing N-bromosuccinimide as a replacement for N-chlorosuccinimide, andsubstituting phenyl(3-(2-hydroxy-2-methylpropoxy)-1-phenyl-1H-pyrazol-5-yl)carbamate forphenyl 3-ethoxy-1-phenyl-1H-pyrazol-5-ylcarbamate. MS (apci) m/z=446.1(M+H).

The following compounds prepared according to the method describe forthe preparation of Intermediate 200, using the appropriate aminopyrazole intermediate:

Intermediate # Structure Name Data 204

phenyl 3-(3- methoxypropyl)- 4-methyl-1- phenyl-1H- pyrazol-5-ylcarbamate MS (apci) m/z = 366.1 (M + H). 205

phenyl 3-(1,1- difluoro-2- hydroxyethyl)- 4-methyl-1- phenyl-1H-pyrazol-5- ylcarbamate MS (apci) m/z = 374.1 (M + H). 206

(S)-phenyl 3-(2- hydroxypropyl)- 4-methyl-1- phenyl-1H- pyrazol-5-ylcarbamate MS (apci) m/z = 352.1 (M + H). 207

(R)-phenyl 3-(2- hydroxypropyl)- 4-methyl-1- phenyl-1H- pyrazol-5-ylcarbamate MS (apci) m/z = 352.1 (M + H). 208

phenyl 3-(2- hydroxy-2- methylpropyl)- 4-methyl-1- phenyl-1H- pyrazol-5-ylcarbamate MS (apci) m/z = 366.2 (M + H). 209

phenyl 3-(3- hydroxy- cyclobutyl)-4- methyl-1- phenyl-1H- pyrazol-5-ylcarbamate MS (apci) m/z = 364.2 (M + H). 210

phenyl 3-(2- hydroxyethyl)- 4-methyl-1- phenyl-1H- pyrazol-5-ylcarbamate MS (apci) m/z = 338.1 (M + H). 211

ethyl 4-methyl- 5-(phenoxy- carbonylamino)- 1-phenyl-1H- pyrazole-3-carboxylate MS (apci) m/z = 366.1 (M + H). 212

phenyl 4-methyl- 3-(methyl- carbamoyl)-1- phenyl-1H- pyrazol-5-ylcarbamate MS (apci) m/z = 351.1 (M + H). 213

phenyl 3- carbamoyl-4- methyl-1- phenyl-1H- pyrazol-5- ylcarbamate MS(apci) m/z = 337.1 (M + H). 214

phenyl (4- methyl-3-(5- methyl-1,3,4- oxadiazol-2- yl)-1-phenyl-1H-pyrazol-5- yl)carbamate MS (apci) m/z = 376.1 (M + H). 215

phenyl 4-methyl- 3-(3-methyl- 1,2,4-oxadiazol- 5-yl)-1-phenyl-1H-pyrazol-5- ylcarbamate MS (apci) m/z = 376.1 (M + H). 216

phenyl 4-methyl- 1-phenyl-3-(3- (trifluoromethyl)- 1,2,4-oxadiazol-5-yl)-1H-pyrazol- 5-ylcarbamate MS (apci) m/z = 430.1 (M + H). 217

tert-butyl 4-(5- ((phenoxy- carbonyl)amino)- 1-phenyl-1H- pyrazol-3-yl)-piperidine-1- carboxylate MS (apci) m/z = 463.3 (M + H) 218

phenyl (4- methyl-1- phenyl-3- (tetrahydro- 2H-pyran-4-yl)-1H-pyrazol-5- yl)carbamate MS (apci) m/z = 378.2 (M + H) 219

phenyl (3-(3,5- dimethyl- isoxazol-4-yl)- 1-phenyl-1H- pyrazol-5-yl)-carbamate ¹H NMR (CDCl₃) δ 7.56-7.64 (m, 4H), 7.48-7.52 (m, 1H), 7.40(t, 2H), 7.26 (t, 2H), 7.16 (br s, 2H), 6.71 (br s, 1H), 2.60 (s, 3H)2.46 (s, 3H) 220

phenyl (4- methyl-3-(5- methylisoxazol- 3-yl)-1-phenyl- 1H-pyrazol-5-yl)carbamate ¹H NMR (CDCl₃) δ 7.54 (d, 2H), 7.49 (t, 2H), 7.41 (t,1H), 7.33 (br s, 2H), 7.20 (br s, 1H), 7.08 (br s, 1H), 6.74 (br s, 1H),6.66 (br s, 1H), 6.48 (s, 1H), 2.45 (s, 3H) 2.34 (s, 3H) 221

phenyl (3-(4- cyanotetrahydro- 2H-pyran-4-yl)- 4-methyl-1- phenyl-1H-pyrazol-5-yl)- carbamate ¹H NMR(CDCl₃) δ 7.06-7.56 (m, 9H), 6.75 (br s,1H), 6.51 (s, 1H), 4.04 (d, 2H) 3.89 (t, 2H), 2.20-2.39 (m, 4H), 2.28(s, 3H) 222

(R)-tert-butyl 2- (4-methyl-5- ((phenoxy- carbonyl)- amino)-1-phenyl-1H- pyrazol-3- yl)pyrrolidine- 1-carboxylate MS (apci) m/z =463.2 (M + H) 223

(S)-tert-butyl 2- (4-methyl-5- ((phenoxy- carbonyl)amino)- 1-phenyl-1H-pyrazol-3-yl)- pyrrolidine-1- carboxylate MS (apci) m/z = 463.2 (M + H)224

(R)-tert-butyl 2- (5-((phenoxy- carbonyl)amino)- 1-phenyl- 1H-pyrazol-3-yl)pyrrolidine-1- carboxylate MS (apci) m/z = 449.2 (M + H) 225

(S)-tert-butyl 2- (5-((phenoxy- carbonyl)amino)- 1-phenyl-1H-pyrazol-3-yl)- pyrrolidine-1- carboxylate MS (apci) m/z = 449.2 (M + H)226

tert-butyl 4-((5- ((phenoxy- carbonyl)amino)- 1-phenyl-1H-pyrazol-3-yl)- methoxy)- piperidine-1- carboxylate MS (apci) m/z = 493.2(M + H) 227

phenyl (3- (hydroxymethyl)- 1-phenyl-1H- pyrazol-5-yl)- carbamate MS(apci) m/z = 310.1 (M + H)

Intermediate 228

tert-butyl4-((4-chloro-5-((phenoxycarbonyl)amino)-1-phenyl-1H-pyrazol-3-yl)methoxy)piperidine-1-carboxylate

To a suspension of tert-butyl4-((5-(phenoxycarbonylamino)-1-phenyl-1H-pyrazol-3-yl)methoxy)piperidine-1-carboxylate(Intermediate 226), 98.5 mg, 0.200 mmol) in DCM (2.0 mL) was addedpyridinium 4-methylbenzenesulfonate (PPTS) (5.03 mg, 0.020 mmol) andN-chlorosuccinimide (40.1 mg, 0.300 mmol). The resulting solution wasstirred at ambient temperature for 8 days. The mixture was diluted withwater and CH₂Cl₂, the organic layer was separated and the aqueous wasextracted with CH₂Cl₂ (2×). The combined organic fractions were driedover MgSO₄, filtered and concentrated. The residue was purified bysilica chromatography using 30-40% EtOAc/hexanes gradient elution toafford the title compound as an orange oil (73.5 mg, 70% yield). MS(apci) m/z=527.2 (M+H).

Intermediate 229

Phenyl (4-chloro-3-(hydroxymethyl)-1-phenyl-1H-pyrazol-5-yl)carbamate

Prepared from phenyl 3-(hydroxymethyl)-1-phenyl-1H-pyrazol-5-ylcarbamate(Intermediate 227) using the procedure outlined for the preparation oftert-butyl4-((4-chloro-5-((phenoxycarbonyl)amino)-1-phenyl-1H-pyrazol-3-yl)methoxy)piperidine-1-carboxylate(Intermediate 228). In this instance, the compound was isolated a whitesolid (108 mg, 28%). MS (apci) m/z=344.0 (M+H).

Intermediate 230

Phenyl (4-bromo-3-(hydroxymethyl)-1-phenyl-1H-pyrazol-5-yl)carbamate

To a suspension of phenyl3-(hydroxymethyl)-1-phenyl-1H-pyrazol-5-ylcarbamate (Intermediate 227,100 mg, 0.323 mmol) in CH₂Cl₂ (1.6 mL) was added pyridinium4-methylbenzenesulfonate (PPTS) (8.12 mg, 0.0323 mmol) andN-bromosuccinimide (86.3 mg, 0.485 mmol). The reaction mixture wasstirred for 16 hours at ambient temperature. The resulting suspensionwas filtered and the collected solid washed briefly with CH₂Cl₂ anddried in vacuum to afford the title compound a white solid (48.5 mg,39%). MS (apci) m/z=388.0 (M+H).

The following pyrazole intermediates were made according to the methodsdescribed for the preparation of Intermediate 228, 229 or 230.

MS (apci) Intermediate Structure Name m/z 231

phenyl (4-chloro-3- (methoxymethyl)-1- phenyl-1H-pyrazol- 5-yl)carbamate358.1 (M + H) 232

phenyl (4-bromo-3- (methoxymethyl)- 1-phenyl-1H- pyrazol-5-yl)-carbamate 402.2 (M + H) 233

phenyl (4-chloro-3- (1,1-difluoro-2- hydroxyethyl)-1- phenyl-1H-pyrazol-5-yl)carbamate 394.1 (M + H) 234

phenyl (4-chloro-3- (2-hydroxy-2- methylpropyl)-1- phenyl-1H-pyrazol-5-yl)carbamate 386.1 (M + H) 235

(S)-phenyl (4- chloro-3-(2- hydroxypropyl)- 1-phenyl-1H- pyrazol-5-yl)-carbamate 372.1 (M + H) 236

(R)-phenyl (4- chloro-3-(2- hydroxypropyl)- 1-phenyl-1H- pyrazol-5-yl)-carbamate 372.1 (M + H) 237

(R)-phenyl (4- bromo-3-(2- hydroxypropyl)- 1-phenyl-1H- pyrazol-5-yl)-carbamate 416.0 (M + H) 238

phenyl (4-chloro- 3-(3-hydroxy- cyclobutyl)-1- phenyl-1H-pyrazol-5-yl)carbamate 384.1 (M + H) 239

phenyl 4-chloro-3- (3-methyl-1,2,4- oxadiazol-5-yl)-1-phenyl-1H-pyrazol- 5-ylcarbamate 396.0 (M + H) 240

phenyl (4-chloro-3- (2-hydroxy-2-methylpropoxy)-1- phenyl-1H-pyrazol-5-yl)carbamate 446.1 (M + H) 241

phenyl (4-chloro-3- (2-hydroxy-2- methylpropoxy)-1- phenyl-1H-pyrazol-5-yl)carbamate 388.1 (M + H) 242

phenyl (4-bromo- 3-(2-hydroxy-2- methylpropoxy)- 1-phenyl-1H-pyrazol-5-yl)- carbamate 433.0 (M + H) 243

ethyl 4-bromo-5- ((phenoxycarbonyl)- amino)-1-phenyl- 1H-pyrazole-3-carboxylate 430.0 (M + H)

Intermediate 245

5-methyl-3-phenyl-1-(pyrazin-2-yl)-1H-pyrazol-4-amine Step A:2-(5-methyl-4-nitroso-3-phenyl-1H-pyrazol-1-yl)pyrazine

To a solution of 2-hydrazinylpyrazine (0.485 g, 4.40 mmol) in HOAc (6mL) was added (2-(hydroxyimino)-1-phenylbutane-1,3-dione (0.765 g, 4.00mmol) in small portions over 2 minutes. The mixture was stirred for 5minutes and the resulting light orange suspension was stirred at 60° C.for 6 hours. EtOH (1 mL) was added and the mixture was heated at 60° C.for an additional 6 hours. The resulting dark green suspension wascooled to ambient temperature and the mixture was diluted with H₂O (30mL). The green suspension was stirred for 1 hour and the solid wascollected via vacuum filtration. The collected solid was washed with H₂Oand dried in vacuum. The solid was suspended in EtOH (25 mL) andconcentrated HCl (500 μL) was added. The mixture was heated at refluxfor 20 hours, cooled to ambient temperature and diluted with chilled H₂O(75 mL). The mixture was treated with 1M NaOH to pH=7 and was extractedwith Et₂O (3×). The combined extracts were washed with saturated NaCland dried over MgSO₄. The dried solution was filtered through packedCelite® and concentrated. The residual green-yellow solid was purifiedon a SiO₂ column using step gradient elution (25% CH₂Cl₂, 50%EtOAc/hexanes) to furnish the title compound as a turquoise solid (325mg, 31%). MS (apci) m/z=266.1 (M+H).

Step B: 5-methyl-3-phenyl-1-(pyrazin-2-yl)-1H-pyrazol-4-amine

To a mixture of 2-(5-methyl-4-nitroso-3-phenyl-1H-pyrazol-1-yl)pyrazine(325 mg, 1.04 mmol) and Zn dust (340 mg, 5.21 mmol) in EtOH (10 mL) wasadded concentrated HCl (95.5 μL, 1.15 mmol). The mixture was stirred atambient temperature for 17 hours, then at 65° C. for 3 hours. Themixture was cooled to ambient temperature and was filtered throughpacked Celite® eluting with MeOH. The eluent was concentrated, and theresidue was treated with H₂O and mixed. The resulting orange suspensiontreated with 2M HCl to pH=1 and the mixture was extracted with Et₂O(3×). The aqueous portion was treated with 2M NaOH to pH=8 and extractedwith EtOAc (3×). The combined EtOAc extracts were washed with saturatedNaCl and dried over MgSO₄/activated carbon. The solution was elutedthrough a SiO₂ plug eluting with EtOAc. The eluent was concentrated togive the title compound as a light yellow wax (33 mg, 13%). MS (esi)m/z=252.2 (M+H).

Intermediate 246

1,5-dimethyl-3-phenyl-1H-pyrazol-4-amine Step A:1,5-dimethyl-4-nitroso-3-phenyl-1H-pyrazole

To a solution of methylhydrazine (0.484 g, 10.5 mmol) in HOAc (10 mL)was added 2-(hydroxyimino)-1-phenylbutane-1,3-dione (2.01 g, 10.5 mmol)in small portions over 5 minutes. The reaction mixture was heated at 60°C. for 1 hour and was cooled to ambient temperature. Et₂O (50 mL) andH₂O (10 mL) were added to the mixture followed by slow addition ofsaturated Na₂CO₃ until pH=8 was obtained. The organic layer was removedand the aqueous layer was extracted with Et₂O (2×). The combined organicfractions were dried over Na₂SO₄, filtered and concentrated. The residuewas purified by silica gel chromatography (1:5 EtOAc/hexanes) to givethe title compound as a green solid (1.32 g, 63%). MS (apci) m/z=202.1(M+H).

Step B: 1,5-dimethyl-3-phenyl-1H-pyrazol-4-amine

To a solution of 1,5-dimethyl-4-nitroso-3-phenyl-1H-pyrazole (1.32 g,6.60 mmol) in MeOH (50 mL) was added Pd(OH)₂ on carbon (200 mg, 20 wt %,0.286 mmol) and the reaction mixture was shaken under 50 psi of H₂ for 3hours at ambient temperature. The reaction mixture was evacuated, purgedwith N₂ filtered through a pad of Celite® with MeOH elution. The eluentwas concentrated and the residue dried in vacuum to provide the titlecompound as a tan solid (1.23 g, 100%). MS (apci) m/z=188.1 (M+H).

Intermediate 247

1-isopropyl-5-methyl-3-phenyl-1H-pyrazol-4-amine

The title compound was prepared according to the method described forIntermediate 246, using isopropylhydrazine hydrochloride in place ofmethylhydrazine in Step A to provide 620 mg (57%) of the title compoundover 2 steps. MS (apci) m/z=216.1 (M+H).

Intermediate 248

5-methyl-3-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-amine Step A:5-methyl-4-nitroso-3-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole

The title compound was prepared using (2,2,2-trifluoroethyl)hydrazine inplace of methylhydrazine in Step A of the procedure described for thepreparation of 1,5-dimethyl-3-phenyl-1H-pyrazol-4-amine (Intermediate246). The compound was isolated as a green solid (999 mg, 71%). ¹H NMR(CDCl₃) δ 7.60-7.73 (m, 5H), 4.70 (q, 2H), 2.27 (t, 3H).

Step B: 5-methyl-3-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-amine

To a mixture of5-methyl-4-nitroso-3-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole (50 mg,0.186 mmol) and Zn dust (60.7 mg, 0.929 mmol) in EtOH (0.4 mL) was addedconcentrated HCl (17.0 μL, 0.204 mmol) and the mixture was heated atreflux for 3 hours. The mixture was cooled to ambient temperature andwas diluted with MeOH and filtered. The filtrate was concentrated andthe residue was diluted in water. The aqueous mixture was treated withsaturated NaHCO₃ until pH=10 was achieved. The mixture was extractedwith DCM (3×) and the combined extracts were dried over Na₂SO₄, filteredand concentrated afford the title compound as a yellow oil (47.1 mg,99.4% yield). MS (apci) m/z=256.1 (M+H).

Intermediate 249

1-ethyl-5-methyl-3-phenyl-1H-pyrazol-4-amine Step A:1-ethyl-5-methyl-4-nitroso-3-phenyl-1H-pyrazole

The title compound was prepared according to the procedure described forthe preparation of Intermediate 246, using ethylhydrazine oxalate inplace of methylhydrazine in Step A.1-Ethyl-5-methyl-4-nitroso-3-phenyl-1H-pyrazole was isolated as a greenoil (288 mg, 26%). ¹H NMR (CDCl₃) δ 8.19 (d, 2H), 7.46-7.50 (m, 3H),4.15 (q, 2H), 2.43 (s, 3H), 1.50 (t, 3H). The minor regioisomer,1-ethyl-3-methyl-4-nitroso-5-phenyl-1H-pyrazole, was also obtained as ablue-green solid (165 mg, 15%). ¹H NMR (CDCl₃) δ 7.71 (dd, 2H), 7.59 (m,3H), 4.17 (q, 2H), 2.28 (s, 3H), 1.51 (t, 3H).

Step B: 1-ethyl-5-methyl-3-phenyl-1H-pyrazol-4-amine

Prepared according to the procedure described for the preparation ofIntermediate 248, using 1-ethyl-5-methyl-4-nitroso-3-phenyl-1H-pyrazolein Step B, the title compound was isolated as a light purple solid (281mg, 104%). MS (apci) m/z=202.1 (M+H).

Intermediate 250

1-ethyl-3-methyl-5-phenyl-1H-pyrazol-4-amine

Prepared according to the procedure described for the preparation ofIntermediate 249, using 1-ethyl-3-methyl-4-nitroso-5-phenyl-1H-pyrazolein Step A. The title compound was prepared according to Step B. Thecompound was isolated as a colorless oil (82.4 mg, 52.5%) afterpurification by reverse-phase chromatography. MS (apci) m/z=202.1 (M+H).

Intermediate 251

1-methyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-amine Step A:4,4,4-trifluoro-2-(hydroxyimino)-1-phenylbutane-1,3-dione

A solution of 4,4,4-trifluoro-1-phenylbutane-1,3-dione (5.00 g, 23.1mmol) in HOAc (46.3 mL) was chilled to 10° C. and sodium nitrite (1.84g, 26.6 mmol) in water (6.0 mL) was added. The mixture was stirred atambient temperature for 90 minutes and was diluted with H₂O (150 mL).The mixture was extracted with Et₂O (3×) and the combined organicfractions were carefully washed with saturated NaHCO₃ until pH=9. TheEt₂O solution was washed with H₂O and saturated NaCl and was dried overMgSO₄. The dried solution was filtered and concentrated to afford thetitle compound as a yellow foam (4.21 g, 74.2% yield). MS (apci)m/z=244.1 (M−H).

Step B: 4-nitroso-3-phenyl-5-(trifluoromethyl)-1H-pyrazole

A solution of hydrazine monohydrate (0.204 g, 4.08 mmol) in EtOH (5 mL)was cooled to 0° C. and4,4,4-trifluoro-2-(hydroxyimino)-1-phenylbutane-1,3-dione (1.00 g, 4.08mmol) in EtOH (15 mL) was added. The reaction mixture was stirred atambient temperature for 3 hours, excess powdered MgSO₄ was added and themixture was heated at 60° C. for 16 hours. The mixture was cooled toambient temperature, filtered and concentrated to afford the crude titlecompound as a green solid (78.7 mg, 8.0%) that was taken directly to thenext step. MS (apci) m/z=240.0 (M−H).

Step C: 1-methyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-amine

To a solution of 4-nitroso-3-phenyl-5-(trifluoromethyl)-1H-pyrazole(78.7 mg, 0.326 mmol) in DMF (1.6 mL) was added NaH (14.4 mg, 0.359mmol) and the mixture was stirred at ambient temperature for 30 minutes.The mixture was treated with methyl iodide (40.6 μL, 0.653 mmol) andstirred for 17 hours. The reaction mixture was directly purified byreverse phase HPLC using 20-100% acetonitrile/water gradient elution toprovide a light blue solid (40.2 mg). The solid was dissolved in EtOH(0.35 mL) and was subjected to the reduction procedure described in StepB of the preparation of5-methyl-3-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-amine(Intermediate 248). The title compound was obtained as white solid (25.1mg, 66.1%).

Intermediate 252

1-methyl-3-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-amine Step A:1-methyl-4-nitroso-3-phenyl-5-(trifluoromethyl)-1H-pyrazole

To a solution of methylhydrazine (0.214 mL, 4.08 mmol) in EtOH (20 mL)was added 4,4,4-trifluoro-2-(hydroxyimino)-1-phenylbutane-1,3-dione(Intermediate 251, Step A; 1.00 g, 4.079 mmol). The reaction mixture wasstirred at ambient temperature for 1 hour and excess MgSO₄ was added.The mixture was stirred at 60° C. for 48 hours and was cooled to ambienttemperature. The mixture was filtered and the filtrate concentrated to agreen residue. The residue was purified by silica gel chromatographyusing a 10-30% EtOAc/hexanes gradient for elution to provide the titlecompound as a green solid (482 mg, 46%). ¹H NMR (CDCl₃) δ 7.89 (d, 2H),7.45-7.52 (m, 3H), 4.15 (s, 3H).

Step B: 1-methyl-3-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-amine

Prepared from1-methyl-4-nitroso-3-phenyl-5-(trifluoromethyl)-1H-pyrazole according tothe method described for the preparation of Intermediate 248, Step B.The title compound was obtained as white solid (309 mg, 68%). ¹H NMR(CDCl₃) δ 7.65 (d, 2H), 7.45 (t, 2H), 7.35 (t, 1H), 3.93 (s, 3H), 3.52(br s, 2H).

Intermediate X1

trans-1-amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol Step A:Preparation of 4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-ol

To a suspension of sodium borohydride (3.12 g, 82.5 mmol) in 4:1THF:MeOH (250 mL) was added 4,4-dimethyl-3,4-dihydronaphthalen-1(2H)-one(13.1 g, 75.0 mmol) dropwise over 15 minutes. The mixture was stirred atambient temperature for 15 minutes and was quenched with 1M NaOH (50mL). After stirring for 15 minutes, the mixture was concentrated and theaqueous residue was diluted with 1M NaOH (50 mL) and H₂O (50 mL). Themixture was extracted with hexanes (3×) and the combined extracts washedwith H₂O and saturated NaCl. The organic portion was dried overMgSO₄/activated charcoal, filtered through packed Celite® andconcentrated to provide the crude product as a faint yellow syrup afterdrying in vacuum (11.8 g, 89%). ¹H NMR (CDCl₃) δ 7.41 (dd, J=7.6, 1.6Hz, 1H), 7.33 (dd, J=7.9, 1.5 Hz, 1H), 7.25 (dt, J=7.3, 1.6 Hz, 1H),7.18 (dd, J=7.5, 1.5 Hz, 1H), 4.72 (dd, J=5.5, 5.1 Hz, 1H), 2.11-2.03(m, 1H), 1.93-1.83 (m, 2H), 1.73 (br s, 1H), 1.63-1.57 (m, 1H), 1.33 (s,3H), 1.24 (s, 3H) ppm.

Step B: Preparation of 1,1-dimethyl-1,2-dihydronaphthalene

To a solution of crude 4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-ol(11.3 g, 64.1 mmol) in dry benzene (150 mL) was added MP-TsOH (0.788 g,3.21 mmol, 4.07 mmol/g) and the mixture was stirred for 18 hours.Molecular sieves (4 angstrom, 10 g) and a second charge of MP-TsOH (0.80g) were added and the mixture was stirred 6 hours. The mixture wasfiltered through a SiO₂ plug capped with a MgSO₄ layer (benzene elution)and concentrated. The residue was purified on a SiO₂ column (hexaneselution) to give the product as a colorless oil (4.54 g, 45%). ¹H NMR(CDCl₃) δ 7.29 (d, J=7.1 Hz, 1H), 7.20-7.12 (m, 2H), 7.04 (dd, J=7.2,1.6 Hz, 1H), 6.45 (d, J=9.6 Hz, 1H), 5.93 (app. dt, J=9.6, 4.4 Hz, 2H),2.24 (dd, J=4.4, 1.8 Hz, 2H), 1.24 (s, 6H) ppm.

Step C: Preparation of3,3-dimethyl-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirene

To a solution of 1,1-dimethyl-1,2-dihydronaphthalene (2.64 g, 14.5 mmol)in toluene (60 mL) was added mCPBA (4.29 g, 17.4 mmol) and the reactionmixture was stirred at ambient temperature for 4.5 hours. The mixturewas eluted through a SiO₂ plug capped with a layer of MgSO₄ (toluene forelution) and concentrated to provide the title compound as a colorlessoil after drying in vacuum (1.62 g, 64%). ¹H NMR (CDCl₃) δ 7.44-7.13 (m,4H), 3.84 (d, J=4.2, 1H), 3.72 (ddd, J=4.2, 2.1, 2.1, 1H), 2.21 (dd,J=15, 2.6 Hz, 1H), 1.83 (d, J=15 Hz, 1H), 1.35 (s, 3H), 1.31 (s, 3H)ppm.

Step D: Preparation oftrans-1-amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol

A sealed pressure vessel was charged with3,3-dimethyl-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirene (1.60 g, 8.26mmol), 7M NH₃ in MeOH (30 mL) and concentrated NH₄OH (30 mL). Thereaction vessel was sealed and the reaction mixture heated at 70° C. for16 hours. The reaction was cooled to ambient temperature andconcentrated to an aqueous mixture. The mixture was diluted with H₂O (50mL) and extracted with EtOAc (3×). The extracts were combined and washedwith H₂O (2×) and saturated NaCl. The solution was dried overMgSO₄/activated charcoal, filtered and concentrated. The residual solidwas washed with hexanes and dried in vacuum to provide the titlecompound as a white solid (1.17 g, 74%). ¹H NMR (CDCl₃) δ 7.46 (dd, 6.4,4.7 Hz, 1H), 7.28 (m, 1H), 7.22 (m, 2H), 3.63 (m, 2H), 2.20 (br s, 3H),1.99 (dd, J=13, 2.8 Hz, 1H), 1.75 (dd, J=12, 12 Hz, 1H), 1.35 (s, 3H),1.31 (s, 3H) ppm.

Intermediate X2

(1R,2R)-1-amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol

The title compound was isolated as a white solid from separation ofracemic trans-1-amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol(Intermediate X1) using preparative chiral HPLC (Chiral Tech OD-H®, 5%EtOH/hexane, Peak 1).

Intermediate X3

(1 S,2S)-1-amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol

The title compound was isolated as a white solid from separation ofracemic trans-1-amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol(Intermediate X1) using preparative chiral HPLC (Chiral Tech OD-H®, 5%EtOH/hexane, Peak 2).

Intermediate X4

trans-1-amino-7-chloro-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-olStep A: Preparation of7-bromo-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-ol

7-bromo-4,4-dimethyl-3,4-dihydronaphthalen-1(2H)-one (1.60 g, 6.32 mmol)was dissolved in MeOH (100 mL) and NaBH₄ (0.287 g, 7.58 mmol) was addedin small portions. The reaction was stirred at ambient temperature for 1hour and partially concentrated in vacuo. 2N NaOH (50 mL) was added andthe mixture was extracted with EtOAc (2×100 mL), filtered through phaseseparator paper and concentrated to afford7-bromo-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-ol (1.60 g, 6.27mmol, 99.2% yield). MS (apci) m/z=255.1; 257.1 (M+H).

Step B: Preparation of 6-bromo-1,1-dimethyl-1,2-dihydronaphthalene

7-bromo-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-ol (1.60 g, 6.27mmol) and MP-TsOH (1.17 g, 6.27 mmol) were combined in 50 mL of tolueneand left to stand overnight. The reaction was filtered, concentrated andpurified by silica gel column using 100% hexanes as the eluent to afford6-bromo-1,1-dimethyl-1,2-dihydronaphthalene (520 mg, 2.19 mmol, 35.0%yield). ¹H NMR (CDCl₃) δ 7.25-7.30 (m, 1H), 7.12-7.17 (m, 2H), 6.35-6.39(m, 1H), 5.95-6.01 (m, 1H), 2.22-2.25 (m, 2H), 1.24 (s, 6H) ppm.

Step C: Preparation of 6-chloro-1,1-dimethyl-1,2-dihydronaphthalene

6-bromo-1,1-dimethyl-1,2-dihydronaphthalene (200 mg, 0.843 mmol) wasdissolved in THF (10 mL) and cooled to −78° C. A solution of tert-BuLiin pentane (1637 μL, 2.78 mmol) was added dropwise and the reaction wasstirred at −78° C. for 20 minutes. 1,1,1,2,2,2-hexachloroethane (477 μL,4.22 mmol) was added and the reaction was allowed to warm to ambienttemperature overnight, quenched with brine (10 ml) and extracted withEtOAc (2×25 mL). The combined organic extracts were filtered throughphase separator paper and concentrated. The crude product was purifiedby silica gel column (100% hexanes) to afford6-chloro-1,1-dimethyl-1,2-dihydronaphthalene (17 mg, 0.09 mmol, 10.5%yield). ¹H NMR (CDCl₃) δ 7.18-7.22 (m, 1H), 7.11-7.14 (m, 1H), 6.99-7.01(m, 1H), 6.35-6.40 (m, 1H), 5.95-6.01 (m, 1H), 2.22-2.26 (m, 2H), 1.24(s, 6H) ppm.

Step D: Preparation oftrans-1-amino-7-chloro-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol

6-chloro-1,1-dimethyl-1,2-dihydronaphthalene (15 mg, 0.08 mmol) wasdissolved in DCM (5 mL) and NaHCO₃ (saturated aqueous, 5 ml) and stirredat 0° C. mCPBA (20 mg, 0.08 mmol) was added and the reaction was allowedto warm to ambient temperature and stirred for 3 days. The mixture wasextracted with several portions of DCM in a phase separator frit,concentrated, and taken up in concentrated ammonium hydroxide (906 μL,8.1 mmol). The reaction was stirred at ambient temperature overnight andthen in a 100° C. sand bath for 3 h. The reaction was cooled andconcentrated to affordtrans-1-amino-7-chloro-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol(21 mg). This material contained some mCPBA-derived impurities but wasused in subsequent reactions without purification. MS (apci) m/z=226.1(M+H).

Intermediate X5

trans-1-amino-1,2,3,4-tetrahydronaphthalen-2-ol Step A: Preparation of1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirene

1,2-dihydronaphthalene (2.00 g, 15.4 mmol) was dissolved in DCM (75 mL)and saturated aqueous NaHCO₃ (75 mL) and cooled to 0° C. mCPBA (4.17 g,16.9 mmol) was added and the reaction was allowed to warm to ambienttemperature overnight. The layers were separated and the aqueous layerwas extracted with EtOAc (100 mL). The combined organic extracts werefiltered through phase separator paper and concentrated to afford1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirene (2.20 g, 15.0 mmol, 98.0%yield). MS (apci) m/z=147.1 (M+H).

Step B: Preparation of trans-1-amino-1,2,3,4-tetrahydronaphthalen-2-ol

1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirene (1.00 g, 6.8 mmol) and NH₄OH(4.8 g, 136 mmol) were combined in a sealed tube and heated at 60° C.for 3 hours. The precipitate that formed was collected and washed withwater and ether to affordtrans-1-amino-1,2,3,4-tetrahydronaphthalen-2-ol (122 mg, 0.7475 mmol,10.93% yield). MS (apci) m/z=147.1 (M-NH₃).

Intermediate X6

trans-1-amino-7-(methoxymethyl)-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-olStep A: Preparation of7-(methoxymethyl)-4,4-dimethyl-3,4-dihydronaphthalen-1(2H)-one

Potassium methoxymethyltrifluoroborate (1.20 g, 7.90 mmol),7-bromo-4,4-dimethyl-3,4-dihydronaphthalen-1(2H)-one (1.00 g, 3.95mmol), Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (0.645 g, 0.790 mmol) and Cs₂CO₃ (6.44 g, 19.8mmol) were combined in dioxane (2 mL) and water (0.5 mL) and degassed bybubbling N₂ through the solution for 10 minutes. The reaction was thensealed in a glass tube and heated in a 100° C. sand bath for 6 hours andthen in a 120° C. sand bath for 15 hours. The reaction was cooled,poured into brine (50 mL) and extracted with EtOAc (2×100 mL). Thecombined organic extracts were concentrated and purified by silica gelcolumn (0-10% EtOAc/hexanes) to afford7-(methoxymethyl)-4,4-dimethyl-3,4-dihydronaphthalen-1(2H)-one (162 mg,0.742 mmol, 18.8% yield). MS (apci) m/z=219.1 (M+H).

Step B: Preparation of7-(methoxymethyl)-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-ol

7-(methoxymethyl)-4,4-dimethyl-3,4-dihydronaphthalen-1(2H)-one (210 mg,0.962 mmol) was dissolved in MeOH (20 mL) and NaBH₄ (54.6 mg, 1.44 mmol)was added in small portions. The reaction was stirred at ambienttemperature for 1 hour and partially concentrated. 2N NaOH (20 mL) wasadded and the mixture was extracted with EtOAc (2×50 mL), filteredthrough phase separator paper and concentrated to afford7-(methoxymethyl)-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-ol (203mg, 0.921 mmol, 95.8% yield). ¹H NMR (CDCl₃) δ 7.38-7.40 (m, 1H),7.30-7.34 (m, 1H), 7.20-7.25 (m, 1H), 4.71-4.75 (m, 1H), 4.42 (s, 2H),3.39 (s, 3H), 2.02-2.12 (m, 1H), 1.82-1.93 (m, 2H), 1.56-1.64 (m, 1H),1.32 (s, 3H), 1.24 (s, 3H) ppm.

Step C: Preparation of6-(methoxymethyl)-1,1-dimethyl-1,2-dihydronaphthalene

7-(methoxymethyl)-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-ol (130mg, 0.590 mmol) was dissolved in 10 ml of dry ether and Martin Sulfurane(516 mg, 0.767 mmol) added. The reaction was stirred at ambienttemperature overnight, 5 mL of 2M saturated aqueous Na₂CO₃ added and thereaction was stirred for 1 hour and filtered through Celite®. Brine wasadded to the filtrate and the mixture was extracted with severalportions of EtOAc. The combined organic extracts were filtered throughphase separator paper, concentrated and purified by silica gel column(0-10% EtOAc/hexanes) to afford6-(methoxymethyl)-1,1-dimethyl-1,2-dihydronaphthalene (100 mg, 0.49mmol, 83.8% yield). MS (apci) m/z=203.1 (M+H).

Step D: Preparation oftrans-1-amino-7-(methoxymethyl)-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol

6-(methoxymethyl)-1,1-dimethyl-1,2-dihydronaphthalene (100 mg, 0.494mmol) was dissolved in DCM (10 mL) and saturated aqueous NaHCO₃ (10 ml)and stirred at 0° C. mCPBA (183 mg, 0.742 mmol) was added and thereaction was allowed to warm to ambient temperature overnight. Themixture was extracted with several portions of DCM in a phase separatorfrit, concentrated, and taken up in concentrated ammonium hydroxide(2623.2 μL, 45.810 mmol). The reaction was stirred in a 60° C. sand bathfor 2 hours, cooled and concentrated to affordtrans-1-amino-7-(methoxymethyl)-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol(100 mg, 0.42 mmol, 88% yield for two steps). This material containedsome impurities but was used in subsequent reactions withoutpurification. MS (apci) m/z=219.1 (M-NH₃).

Intermediate X7

trans-5-amino-6,7,8,9-tetrahydro-5H-benzo[7] annulen-6-ol

trans-5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-ol was synthesizedfrom 1-Benzosuberone in 23.9% overall yield using the method asdescribed for Intermediate X1, Steps A-D. The obtainedtrans-5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-ol contained someimpurities but was used in subsequent reactions without purification MS(apci) m/z=178.1 (M+H).

Intermediate X8

6-(methoxymethyl)-1-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-4-amineStep A: Preparation of2,2-dimethoxy-N-(1-(4-(methoxymethyl)phenyl)ethyl)ethanamine

1-(4-(methoxymethyl)phenyl)ethanone (500 mg, 3.05 mmol) and2,2-dimethoxyethanamine (480 mg, 4.57 mmol) were combined in 3 mL ofCHCl₃ and stirred for 15 minutes. Na(OAc)₃BH (839 mg, 3.96 mmol) wasadded and the reaction was stirred for 2 hours. AcOH (1 drop) was addedand the reaction was stirred at ambient temperature overnight, quenchedwith water (3 mL) and extracted with DCM (3×10 mL) in a Phase Separatorfrit. The combined organic extracts were concentrated to afford2,2-dimethoxy-N-(1-(4-(methoxymethyl)phenyl)ethyl)ethanamine (610 mg,2.41 mmol, 79.1% yield). MS (apci) m/z=254.2 (M+H).

Step B: Preparation ofN-(2,2-dimethoxyethyl)-2,2,2-trifluoro-N-(1-(4-(methoxymethyl)phenyl)ethyl)ethanamine

2,2-dimethoxy-N-(1-(4-(methoxymethyl)phenyl)ethyl)ethanamine (250 mg,0.987 mmol), NEt₃ (413 μl, 2.96 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (275 mg, 1.18 mmol) were combined and stirredat ambient temperature overnight, at 60° C. for 24 hours and then at100° C. for 24 hours. The reaction was loaded onto a samplet andpurified by reverse phase column (0-80% Acetonitrile/H₂O) to affordN-(2,2-dimethoxyethyl)-2,2,2-trifluoro-N-(1-(4-(methoxymethyl)phenyl)ethyl)ethanamine(278 mg, 0.829 mmol, 84.0% yield). MS (apci) m/z=254.2 (M-MeOH).

Step C: Preparation of6-(methoxymethyl)-1-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-4-ol

N-(2,2-dimethoxyethyl)-2,2,2-trifluoro-N-(1-(4-(methoxymethyl)phenyl)ethyl)ethanamine(330 mg, 0.984 mmol) and perchloric acid (70% in water, 2 mL) werecombined and stirred at ambient temperature for 4 hours. The reactionwas poured into a mixture of ice and 2N NaOH (50 mL) and extracted withseveral portions of EtOAc, filtered through PS paper and concentrated.The mixture was purified by reverse phase column using 0-70%acetonitrile/H₂O as the eluent to afford6-(methoxymethyl)-1-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-4-ol(143 mg, 0.494 mmol, 50.2% yield) as a ˜1:2 mixture of diastereomers. MS(apci) m/z=290.1 (M+H)

Step D: Preparation of4-azido-6-(methoxymethyl)-1-methyl-2-(2,2,2-trifluoroethyl)

1,2,3,4-tetrahydroisoquinoline:6-(methoxymethyl)-1-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-4-ol(25 mg, 0.086 mmol) was dissolved in DCM (2 mL) and thionyl chloride (13μL, 0.17 mmol) was added. The reaction was stirred at ambienttemperature for 2 h and then at 50° C. for 20 minutes, concentrated, andDMF and NaN₃ (52.8 mg, 0.812 mmol) were added. The reaction was stirredambient temperature for 1 hour and then at 100° C. for 30 minutes. Themixture was loaded onto a samplet and purified by reverse phase columnchromatography using 0-70% acetonitrile/H₂O as the eluent to afford4-azido-6-(methoxymethyl)-1-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline(20 mg, 0.0636 mmol, 78.3% yield). MS (apci) m/z=287.1 (M-N₂).

Step E: Preparation of6-(methoxymethyl)-1-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-4-amine

4-azido-6-(methoxymethyl)-1-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline(20 mg, 0.064 mmol) and 10% Pd/C (6.8 mg, 0.0064 mmol) were mixed in 1mL of MeOH and stirred under a balloon of H₂ for 3 hours. The reactionwas filtered and concentrated to afford6-(methoxymethyl)-1-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-4-amine(18 mg, 0.062 mmol, 98% yield) which was used without purification. MS(apci) m/z=272.1 (M-NH₃).

Intermediate X9

(2′R,3′R)-3′-amino-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2′-olhydrochloride Step A: Preparation of tert-butyl(trans-2′-hydroxy-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-3′-yl)carbamate

To a solution oftrans-3′-amino-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2′-ol(Example 55, Step C, 425 mg, 2.425 mmol) in DCM (15 mL) were added DIEA(845 μL, 4.851 mmol) and Boc₂O (582 mg, 2.668 mmol). The reactionmixture was stirred at ambient temperature for 22 hours, then dilutedwith H₂O (25 mL), extracted with DCM (2×25 mL), and the combined organicphases were washed with brine (40 mL), dried (MgSO₄), filtered, andconcentrated to afford the product as a beige solid (636 mg, 95% yield).

Step B: Preparation oftrans-3′-((tert-butoxycarbonyl)amino)-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2′-ylacetate

To a solution of tert-butyl(trans-2′-hydroxy-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-3′-yl)carbamate(455 mg, 1.65 mmol) in pyridine (4.13 mL, 1.65 mmol) were added DMAP(20.2 mg, 0.165 mmol) then Ac₂O (468 μl, 4.96 mmol). The reactionmixture was stirred at ambient temperature for 17 hours, then wasdiluted with aqueous HCl (1 M, 60 mL), then extracted with DCM (2×50mL). The combined organic phases were washed with H₂O (50 mL), dried(MgSO₄), filtered, concentrated, and dried under high vacuum to affordthe product as a brown solid (477 mg, 91% yield).

Step C: Preparation of(2′R,3′R)-3′-((tert-butoxycarbonyl)amino)-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2′-ylacetate

Racemictrans-3′-((tert-butoxycarbonyl)amino)-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2′-ylacetate (477 mg, 1.503 mmol) was separated by chiral HPLC (Chiral TechOJ-H, 22 mm×250 mm, 5μ particle size, 7.5% ethanol: 92.5% hexanes, 22mL/min, 220 nm). The first peak to elute was collected and concentratedto afford the product as a white solid (168 mg, 35% yield). ¹H NMR(CDCl₃) δ 7.33 (d, 1H), 7.28-7.19 (m, 2H), 6.71 (d, 1H), 5.28 (d, 1H),5.20 (br m, 1H), 4.82 (br m, 1H), 2.07 (s, 3H), 1.48 (s, 9H), 1.25 (m,1H), 1.16 (m, 1H), 1.00 (m, 1H), 0.88 (m, 1H).

Step D: Preparation of tert-butyl((2′R,3′R)-2′-hydroxy-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-3′-yl)carbamate

To a solution of(2′R,3′R)-3′-((tert-butoxycarbonyl)amino)-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2′-ylacetate (168 mg, 0.529 mmol) in MeOH (2 mL) was added K₂CO₃ (109.7 mg,0.794 mmol). The reaction mixture was stirred at ambient temperature for2 hours, then diluted with 20% iPrOH/80% DCM (10 mL), filtered through aplug of silica, rinsing with 20% iPrOH/80% DCM (2×20 mL). The eluent wasconcentrated to afford the product as an off-white solid (145 mg, 99%yield). ¹H NMR (CDCl₃) δ 7.15-7.25 (m, 3H), 6.73 (d, 1H), 5.03 (br s,1H), 4.93 (t, 1H), 4.25 (d, 1H), 1.52 (m, 1H), 1.48 (s, 9H), 1.10 (m,1H), 0.96 (m, 1H), 0.60 (m, 1H).

Step E: Preparation of(2′R,3′R)-3′-amino-2′,3′-dihydrospiro[cyclopropane-11′-inden]-2′-olhydrochloride

To a solution of tert-butyl((2′R,3′R)-2′-hydroxy-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-3′-yl)carbamate(145 mg, 0.527 mmol) in iPrOH (2.5 mL) was added HCl (5-6M in iPrOH,1.05 mL). The reaction mixture was stirred at ambient temperature for 17hours and then concentrated. The solid was diluted with Et₂O (1 mL) andconcentrated (3×), then dried under high vacuum to afford the HCl saltof the product as a pale yellow solid (110 mg, 99% yield). ¹H NMR(CD₃OD) δ 7.43 (dd, 1H), 7.34 (tt, 1H), 7.26 (dt, 1H), 6.87 (br d, 1H),4.51 (d, 1H), 4.25 (d, 1H), 1.41 (m, 1H), 1.16 (m, 1H), 1.02 (m, 1H),0.75 (m, 1H).

Intermediate X10

(2'S,3'S)-3′-amino-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2′-olStep A: Preparation of(2'S,3'S)-3′-((tert-butoxycarbonyl)amino)-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2′-ylacetate

Racemictrans-3′-((tert-butoxycarbonyl)amino)-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2′-ylacetate (Intermediate X9, Step B, 176 mg, 0.555 mmol) was separated bychiral HPLC (Chiral Tech OJ-H, 22 mm×250 mm, 5μ particle size, 7.5%ethanol: 92.5% hexanes, 22 mL/min, 220 nm). The second peak to elute wascollected and concentrated to afford the product as a beige solid (63.4mg, 36% yield). ¹H NMR (CDCl₃) δ 7.32 (d, 1H), 7.21 (m, 2H), 6.70 (d,1H), 5.26 (d, 1H), 5.19 (br s, 1H), 4.80 (br s, 1H), 2.05 (s, 3H), 1.46(s, 9H), 1.24 (m, 1H), 1.13 (m, 1H), 1.00 (m, 1H), 0.86 (m, 1H).

Step B: Preparation of tert-butyl((2'S,3'S)-2′-hydroxy-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-3′-yl)carbamate

To a solution of(2'S,3'S)-3′-((tert-butoxycarbonyl)amino)-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2′-ylacetate (55.4 mg, 0.200 mmol) in MeOH (2 mL) was added K₂CO₃ (41.4 mg,0.300 mmol). The reaction mixture was stirred at ambient temperature for2 hours, then diluted with 20% iPrOH/80% DCM (10 mL), filtered through aplug of silica, rinsing with 20% iPrOH/80% DCM (2×20 mL). The eluent wasconcentrated to afford the product as a pale orange solid (55.4 mg, 100%yield).

Step C: Preparation of(2'S,3'S)-3′-amino-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2′-ol

To a solution of tert-butyl((2'S,3'S)-2′-hydroxy-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-3′-yl)carbamate(55.4 mg, 0.201 mmol) in iPrOH (1.3 mL) was added HCl (5-6M in iPrOH,0.2 mL). The reaction mixture was stirred at ambient temperature for 1hour, and additional HCl (5-6M in iPrOH, 0.2 mL) was added. The reactionmixture was stirred at ambient temperature for 19 hours, and additionalHCl (5-6M in iPrOH, 0.2 mL) was added. The reaction mixture was stirredat ambient temperature for 2 hours, then diluted with saturated aqueousNaHCO₃ (25 mL), extracted with 10% MeOH/90% DCM (3×25 mL), and thecombined organic phases were dried (MgSO₄), filtered, and concentratedto afford the product as a pale blue solid (18.4 mg, 52% yield). ¹H NMR(CD₃OD) δ 7.31 (m, 1H), 7.22 (m, 2H), 6.75 (m, 1H), 4.17 (d, 1H), 3.98(d, 1H), 1.36 (m, 1H), 1.12 (m, 1H), 0.96 (m, 1H), 0.68 (m, 1H).

Intermediate X11

trans-4′-amino-3′,4′-dihydro-2′H-spiro[cyclopropane-1,1′-naphthalen]-3′-olStep A: Preparation of 1-methylene-1,2,3,4-tetrahydronaphthalene

To a suspension of methyltriphenylphosphonium bromide (8.797 g, 24.626mmol) in Et₂O (90 mL) under N₂ was added KOtBu (2.763 g, 24.626 mmol) inseveral portions over 5 minutes. The reaction mixture was stirred atambient temperature for 2 hours, then was cooled to 0° C. and a solutionof 3,4-dihydronaphthalen-1(2H)-one (2.737 mL, 20.522 mmol) in Et₂O (10mL) was added. The reaction mixture was allowed to warm to ambienttemperature and stirred for 2 hours. The reaction mixture was filteredthrough Celite® and rinsed with Et₂O (4×100 mL), and concentrated. Thecrude oil was purified by silica column chromatography, eluting withhexanes, to afford the product as a colorless oil (3.02 g, 102% yield).¹H NMR (CDCl₃) δ 7.64 (m, 1H), 7.16 (m, 2H), 7.09 (m, 1H), 5.47 (dd,1H), 4.95 (dd, 1H), 2.85 (dd, 2H), 2.55 (m, 2H), 1.88 (m, 2H).

Step B: Preparation of3′,4′-dihydro-2′H-spiro[cyclopropane-1,1′-naphthalene]

To a solution of diethyl zinc (1M in hexanes, 31.2 mL, 31.2 mmol) andDCM (80 mL), under N₂ flow and cooled to 0° C., was added a solution ofTFA (2.40 mL, 31.204 mmol) in DCM (10 mL) dropwise over 25 minutes. Atthe end of the addition, DCM (10 mL) was added, and the reaction mixturewas stirred at 0° C. for 30 minutes. Diiodomethane (2.51 mL, 31.204mmol) was added dropwise over 5 minutes, and the reaction mixture wasstirred at 0° C. for 1 hour. A solution of1-methylene-1,2,3,4-tetrahydronaphthalene (3.0 g, 20.803 mmol) in DCM(10 mL) was added dropwise over 5 minutes, then the reaction mixture wasstirred at 0° C. for 2 hours. The reaction mixture was diluted with H₂O(50 mL), stirred for 30 minutes, then filtered through Celite®, rinsingwith DCM (3×50 mL). The phases were separated and the aqueous phaseextracted with DCM (50 mL). The combined organic phases were dried(MgSO₄), filtered, and partially concentrated afford the product as ayellow oil (12.88 g, 389% yield). The product contained both DCM andCH₂1₂ by ¹H NMR analysis and was used in the next step without furtherpurification. ¹H NMR (CDCl₃) δ 7.04 (m, 3H), 6.66 (d, 1H), 5.30 (s, 5H,CH₂Cl₂), 3.87 (s, 10H, CH₂12), 2.88 (dd, 2H), 1.90 (m, 2H), 1.67 (m,2H), 0.96 (m, 2H), 0.78 (m, 2H).

Step C: Preparation of2′H-spiro[cyclopropane-1,1′-naphthalen]-4′(3′H)-one

To a solution of 3′,4′-dihydro-2′H-spiro[cyclopropane-1,1′-naphthalene](3.29 g, 20.791 mmol) in DCM (100 mL) cooled to 0° C. were added CrO₃(0.416 g, 4.158 mmol), then tert-butyl hydroperoxide (43.1 mL, 311.9mmol). The reaction mixture was allowed to warm to ambient temperatureslowly and stirred for 24 hours, then the reaction mixture was dilutedwith MeOH (50 mL) and water (200 mL), then extracted with Et₂O (3×150mL). The combined organic phases were washed with saturated aqueousNaHCO₃ (100 mL) and brine (100 mL), dried (MgSO₄), filtered andconcentrated. The crude oil was purified by silica columnchromatography, eluting with 0-30% acetone/hexanes, to afford theproduct as an orange oil (1.68 g, 47% yield). ¹H NMR (CDCl₃) δ 8.04 (dd,1H), 7.45 (ddd, 1H), 7.25 (m, 1H), 6.83 (dd, 1H), 2.78 (dd, 2H), 1.99(dd, 2H), 1.10 (m, 2H), 0.99 (m, 2H).

Step D: Preparation of3′,4′-dihydro-2′H-spiro[cyclopropane-1,1′-naphthalen]-4′-ol

To a solution of 2′H-spiro[cyclopropane-1,1′-naphthalen]-4′(3′H)-one(1.68 g, 9.755 mmol) in MeOH (32 mL) cooled to 0° C. was added NaBH₄(0.443 g, 11.706 mmol) in several portions over 10 min. The reactionmixture was allowed to warm to ambient temperature slowly and stirredfor 17 hours. The reaction mixture was diluted with H₂O (100 mL) andextracted with DCM (3×100 mL). The combined organic extracts were washedwith brine (50 mL), dried (MgSO₄), filtered, and concentrated to affordthe product as a peachy-orange syrup (927 mg, 55% yield).

Step E: Preparation of 2′H-spiro[cyclopropane-1,1′-naphthalene]

To a solution of3′,4′-dihydro-2′H-spiro[cyclopropane-1,1′-naphthalen]-4′-ol (927 mg,5.320 mmol) in toluene (17 mL) was added TsOH—H₂O (50.6 mg, 0.266 mmol).The reaction mixture was heated to 110° C. for 90 minutes, then cooledto ambient temperature. The reaction mixture was diluted with H₂O (50mL) and extracted with DCM (3×50 mL). The combined organic extracts weredried (MgSO₄), filtered, and concentrated. The crude oil was purified bysilica column chromatography, eluting with hexanes, to afford theproduct as a solution in hexanes and toluene (3.13 g, 377% yield). Theproduct contained both hexanes and toluene by ¹H NMR analysis and wasused in the next step without further purification.

Step F: Preparation oftrans-3′-bromo-3′,4′-dihydro-2′H-spiro[cyclopropane-11′-naphthalen]-4′-ol

To a solution of 2′H-spiro[cyclopropane-1,1′-naphthalene] (100 mg, 0.640mmol) in DMSO (1.3 mL) were added H₂O (115 μL, 6.401 mmol) then NBS (125mg, 0.704 mmol). The reaction mixture was stirred at ambient temperaturefor 21 hours, then was diluted with water (20 mL) and extracted withEt₂O (3×20 mL). The combined organic phases were washed with brine (25mL), dried (MgSO₄), filtered and concentrated. The crude oil waspurified by silica column chromatography, eluting with 0-50%acetone/hexanes, to afford the product as a pale yellow residue (13 mg,8% yield). ¹H NMR (CDCl₃) δ 7.56 (m, 1H), 7.21 (m, 2H), 6.63 (m, 1H),4.99 (d, 1H), 4.49 (ddd, 1H), 2.62 (br s, 1H), 2.53 (dd, 1H), 2.05 (dd,1H), 1.22 (m, 1H), 0.94 (m, 2H), 0.86 (m, 1H).

Step G: Preparation of2′,7b′-dihydro-1a′H-spiro[cyclopropane-1,3′-naphtho[1,2-b]oxirene]

To a solution oftrans-3′-bromo-3′,4′-dihydro-2′H-spiro[cyclopropane-1,1′-naphthalen]-4′-ol(13 mg, 0.0514 mmol) in Et₂O (2.5 mL) was added KOH (140 mg, 2.495mmol). The reaction mixture was stirred at ambient temperature for 23hours, then additional KOH (140 mg, 2.495 mmol) was added. The reactionmixture was stirred at ambient temperature for 3 hours, then wasfiltered, rinsed with Et₂O, and concentrated to afford the product as acolorless oil (18 mg, 204% yield). The product contained Et₂O by NMRanalysis, and was used in the next step without further purification.

Step H: Preparation oftrans-4′-amino-3′,4′-dihydro-2′H-spiro[cyclopropane-1,1′-naphthalen]-3′-ol

To a solution of2′,7b′-dihydro-1a′H-spiro[cyclopropane-1,3′-naphtho[1,2-b]oxirene] (8mg, 0.047 mmol) NH₃ (7N in MeOH, 0.5 mL) was added NH₄OH (0.5 mL). Thereaction mixture was heated to 70° C. for 2.5 hours, then cooled toambient temperature. The reaction mixture was diluted with H₂O (10 mL),acidified with HCl (1 M aqueous, 4 mL), then extracted with Et₂O (10mL), which was discarded. The aqueous phase was then made basic byaddition of aqueous NaOH (4 M aqueous, 0.5 mL), then extracted with 10%MeOH/90% DCM (3×10 mL). The combined organic phases were dried (MgSO₄),filtered, concentrated, and dried under high vacuum to afford theproduct as a beige solid (5.6 mg, 64% yield). ¹H NMR (CDCl₃) δ 7.45 (m,1H), 7.17 (m, 2H), 6.62 (m, 1H), 3.75 (m, 2H), 2.16 (m, 1H), 1.99 (br s,3H), 1.64 (m, 1H), 1.18 (m, 1H), 0.90 (m, 2H), 0.81 (m, 1H).

Intermediate X12

trans-4-aminospiro[chroman-2,1′-cyclobutan]-3-ol Step A:spiro[chroman-2,1′-cyclobutan]-4-one

To a suspension of 1-(2-hydroxyphenyl)ethanone (3.0 g, 22.035 mmol) inMeOH (37 mL) was added pyrrolidine (3.679 mL, 44.070 mmol). The reactionmixture was stirred at ambient temperature for 15 minutes, and thencyclobutanone (1.65 mL, 22.035 mmol) was added. The reaction mixture washeated to 50° C. for 19 hours, then additional cyclobutanone (1.0 mL)was added and the reaction mixture was heated to 65° C. for 5 days. Thereaction mixture was diluted with H₂O (100 mL), extracted DCM (3×100mL), and the combined organic phases were washed with aqueous HCl (1 M,200 mL), then H₂O (200 mL), then brine (200 mL), dried (MgSO₄),filtered, and concentrated. The crude oil was purified by silica columnchromatography, eluting with 0-30% acetone/hexanes, to afford theproduct as an orange oil (2.92 mg, 70% yield). ¹H NMR (CDCl₃) δ 7.85(dd, 1H), 7.47 (ddd, 1H), 6.99 (m, 2H), 2.90 (s, 2H), 2.33 (m, 2H), 2.17(m, 2H), 1.93 (m, 1H), 1.72 (m, 1H).

Step B: spiro[chroman-2,1′-cyclobutan]-4-ol

To a solution of spiro[chroman-2,1′-cyclobutan]-4-one (1.00 g, 5.313mmol) in MeOH (17 mL) cooled to 0° C. was added NaBH₄ (0.241 g, 6.375mmol) in several portions over 10 minutes. The reaction mixture wasallowed to warm to ambient temperature slowly and stirred for 19 hours.The reaction mixture was diluted with H₂O (100 mL) and extracted withDCM (3×100 mL). The combined organic extracts were washed with brine (50mL), dried (MgSO₄), filtered, and concentrated to afford the product asa thick yellow syrup (715 mg, 71% yield). ¹H NMR (CDCl₃) δ 7.38 (dd,1H), 7.17 (ddd, 1H), 6.91 (ddd, 1H), 6.82 (dd, 1H), 4.84 (dd, 1H),2.35-2.23 (m, 4H), 2.13-2.03 (m, 2H), 1.95-1.85 (m, 1H), 1.78-1.66 (m,1H).

Step C: spiro[chromene-2,1′-cyclobutane]

To a solution of spiro[chroman-2,1′-cyclobutan]-4-ol (715 mg, 3.758mmol) in DCM (7.5 mL) were added molecular sieves (350 mg, 4 A,powdered, activated, oven-dried) and MP-TsOH (46 mg, 0.188 mmol). Thereaction mixture was stirred at ambient temperature for 4 days, thenadditional molecular sieves (300 mg, 4 A, powdered, activated,oven-dried) and MP-TsOH (46 mg, 0.188 mmol) were added, and the reactionmixture was stirred at ambient temperature for 17 hours. The reactionmixture was filtered, rinsed with DCM, and concentrated. The crude oilwas purified by silica column chromatography, eluting with 0-25%acetone/hexanes, to afford the product as a pale yellow oil (135 mg, 21%yield). The product was impure by ¹H NMR analysis and was used in thenext step without further purification.

Step D: trans-3-bromospiro[chroman-2,1′-cyclobutan]-4-ol

To a solution of spiro[chromene-2,1′-cyclobutane] (135 mg, 0.784 mmol)in DMSO (1.5 mL) were added H₂O (141 μL, 7.839 mmol) then NBS (153 mg,0.862 mmol). The reaction mixture was stirred at ambient temperature for17 hours, then was diluted with water (20 mL) and extracted with Et₂O(3×20 mL). The combined organic phases were washed with brine (25 mL),dried (MgSO₄), filtered and concentrated. The crude oil was purified bysilica column chromatography, eluting with 0-25% acetone/hexanes, toafford the product as a thick colorless syrup (115 mg, 55% yield). ¹HNMR (CDCl₃) δ 7.37 (dd, 1H), 7.26 (dt, 1H), 7.00 (dd, 1H), 6.94 (dt,1H), 4.98 (d, 1H), 4.45 (d, 1H), 2.74 (m, 1H), 2.43 (m, 1H), 2.35 (m,1H), 2.26 (m, 1H), 2.09 (m, 1H), 1.86 (m, 1H).

Step E: 1a′,7b′-dihydrospiro[cyclobutane-1,2′-oxireno[2,3-c]chromene]

To a solution of trans-3-bromospiro[chroman-2,1′-cyclobutan]-4-ol (115mg, 0.427 mmol) in Et₂O (21 mL) was added KOH (1.2 g, 21.4 mmol). Thereaction mixture was stirred at ambient temperature for 19 hours, thenwas filtered, rinsed with Et₂O, and concentrated to afford the productas a colorless oil (79.8 mg, 99% yield). ¹H NMR (CDCl₃) δ 7.31 (m, 1H),7.21 (m, 1H), 6.91 (m, 1H), 6.83 (m, 1H), 3.90 (m, 2H), 2.55 (m, 2H),2.19 (m, 2H), 1.99 (m, 1H), 1.79 (m, 1H).

Step F: trans-4-aminospiro[chroman-2,1′-cyclobutan]-3-ol

To a hazy solution of1a′,7b′-dihydrospiro[cyclobutane-1,2′-oxireno[2,3-c]chromene] (80 mg,0.425 mmol) in NH₃ (7N in MeOH, 0.5 mL) was added NH₄OH (1 mL). Thereaction mixture was heated to 70° C. for 2 hours, then cooled toambient temperature. The reaction mixture was diluted with H₂O (10 mL),then extracted with 10% MeOH/90% DCM (2×15 mL). The combined organicphases were dried (MgSO₄), filtered, concentrated, and dried under highvacuum to afford the product as a white solid (76 mg, 87% yield). ¹H NMR(CDCl₃) δ 7.35 (m, 1H), 7.16 (m, 1H), 6.94 (m, 1H), 6.84 (m, 1H), 3.79(d, 1H), 3.54 d, 1H), 2.62 (m, 1H), 2.52 (br s, 2H), 2.31 (m, 2H), 2.02(m, 2H), 1.83 (m, 1H).

Intermediate Y1

(S)-4-methyl-3-((4-methylmorpholin-2-yl)methoxy)-1-phenyl-1H-pyrazol-5-amineStep A: Preparation of (S)-tert-butyl2-(((5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)oxy)methyl)morpholine-4-carboxylate

A mixture of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one(Intermediate 2, Step A, 335 mg, 1.77 mmol), (S)-tert-butyl2-(bromomethyl)morpholine-4-carboxylate (496 mg, 1.77 mmol) andpotassium carbonate (612 mg, 4.43 mmol) in dry DMF (15 mL) was heated at70° C. for 45 hours. The reaction mixture was cooled to ambienttemperature and was added to ice-H₂O (10 mL) with dissolving of all ofthe K₂CO₃. The mixture was extracted with 50% EtOAc/hexanes (3×) and thecombined extracts were washed with H₂O (2×) and saturated NaCl. Theorganic portion was dried over MgSO₄/activated charcoal, eluted througha thin SiO₂ plug (50% EtOAc/hexanes) and concentrated to give theproduct as a white foam that was dried in vacuum (418 mg, 61%). MS(apci) m/z=389.3 (M+H).

Step B: Preparation of(S)-4-methyl-3-(morpholin-2-ylmethoxy)-1-phenyl-1H-pyrazol-5-amine

(S)-tert-butyl2-(((5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)oxy)methyl)morpholine-4-carboxylate(332 mg, 0.855 mmol) was dissolved in chilled 5M HCl in iPrOH (10 mL)and the solution was stirred at ambient temperature for 2 hours. Themixture was concentrated and the residual white solid was washed withEt₂O (2×) and dried. The solid was dissolved in H₂O (5 mL) and 2M NaOHwas added to pH=13. The solution was saturated with NaCl(s) and EtOAc (5mL) was added. The biphasic mixture was stirred for 1 hour, the organiclayer removed and the aqueous portion extracted with EtOAc (2×). Thecombined EtOAc fractions were dried over MgSO₄, filtered andconcentrated. The resulting colorless syrup was dried in vacuum toprovide the title compound as a white foam (220 mg, 89%). MS (apci)m/z=289.2 (M+H).

Step C:(S)-4-methyl-3-((4-methylmorpholin-2-yl)methoxy)-1-phenyl-1H-pyrazol-5-amine

A mixture of(S)-4-methyl-3-(morpholin-2-ylmethoxy)-1-phenyl-1H-pyrazol-5-amine (218mg, 0.756 mmol) and NaBH(OAc)₃ (506 mg, 2.27 mmol) in 1,2-DCE (4 mL) wascooled to 0° C. and 37% aqueous formaldehyde (62.5 μL, 0.832 mmol) wasadded. The mixture was stirred for 15 hours during which time thetemperature gradually reached ambient. The mixture was treated withchilled 1.0M NaOH (8 mL) and mixed at ambient temperature for 30minutes. NaCl (s) was added to saturation and the organic layer wasremoved. The aqueous portion was extracted with CH₂Cl₂ (2×) and thecombined organic fractions dried over Na₂SO₄/activated charcoal. Thesolution was filtered through a SiO₂ plug capped with a layer of MgSO₄using CH₂Cl₂, EtOAc then 5% (9:1 MeOH/NH₄OH)/EtOAc for elution. Theproduct pool was concentrated to give the title compound as a colorlesswaxy solid that was dried in vacuum (155 mg, 68%). MS (apci) m/z=303.2(M+H).

Intermediate Y2

(R)-4-methyl-3-((4-methylmorpholin-2-yl)methoxy)-1-phenyl-1H-pyrazol-5-amine

Using (R)-tert-butyl 2-(bromomethyl)morpholine-4-carboxylate in theprocedure described for Intermediate Y1, the title compound was preparedas a white foam (44% over 3 steps). MS (apci) m/z=303.2 (M+H).

Intermediate Y3

4-methyl-3-((1-methylpiperidin-4-yl)methoxy)-1-phenyl-1H-pyrazol-5-amine

Using tert-butyl 4-(bromomethyl)piperidine-1-carboxylate in theprocedure described for Intermediate Y1, the title compound was preparedas a white solid (25% over 3 steps). MS (apci) m/z=301.2 (M+H).

Intermediate Y4

4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-amine

Step A: Preparation of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one: Amixture of ethyl 2-cyanopropanoate (50.5 g, 397.2 mmol) andphenylhydrazine (39 mL, 397.2 mmol) in dioxane (100 mL) was heated at110° C. for 5 days. The cooled mixture was concentrated to ½ volume thencooled in ice and triturated with cold Et₂O. The resulting solids werefiltered, washed extensively with Et2O and dried in vacuo to afford5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one (34.69 g, 46% yield) as afluffy white powder. MS (apci) m/z=190.1 (M+H).

Step B: Preparation of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yltrifluoromethane sulfonate: A suspension of5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one (13.72 g, 72.5 mmol) andN-phenylbis(trifluoromethylsulfonamide) (27.2 g, 76.1 mmol) in DMF (100mL) was treated with DIEA (37.9 mL, 217.5 mmol) and the mixture stirredat ambient temperature for 16 hours. The mixture was partitioned betweensaturated NaHCO₃(400 mL) and EtOAc (200 mL) and the aqueous layer wasextracted with EtOAc (2×200 mL). The combined organic phases were washedwith water (5×50 mL) and brine (50 mL) then dried over Na₂SO₄, filteredand concentrated in vacuo. The residue was purified by silica columnchromatography eluting with 4:1 hexanes/EtOAc, to afford5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl trifluoromethane sulfonate(23.1 g, 99% yield) as a pale yellow solid. MS (apci) m/z=322.0 (M+H).

Step C: Preparation of4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-amine:5-Amino-4-methyl-1-phenyl-1H-pyrazol-3-yl trifluoromethane sulfonate(900 mg, 2.8 mmol),2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (925mg, 4.2 mmol), K₂CO₃ (1.55 g, 11.2 mmol) and Pd(PPh₃)₄(324 mg, 0.28mmol) were combined in toluene (10 mL), water (5 mL) and EtOH (2.5 mL)and warmed to 95° C. in a sealed tube for 16 hours. The cooled mixturewas filtered and the filtrate partitioned between water (50 mL) andEtOAc (50 mL). The aqueous layer was extracted with EtOAc (2×30 mL) andthe combined organic phases were washed with brine (30 mL), dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bysilica column chromatography eluting with 2% MeOH/DCM to afford thetitle compound (533 mg, 72% yield) as a pink solid. MS (apci) m/z=266.1(M+H).

Intermediate Y5

3-(2-methoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-amine

Prepared according to the procedure for Intermediate Y4, substituting2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine for2-methoxypyrimidin-5-ylboronic acid in Step C, to afford the titlecompound (138 mg, 78% yield) as a cream foam. MS (apci) m/z=282.1 (M+H).

Intermediate Y6

3-(2-(dimethylamino)ethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-amine

To a thick-walled pressure reaction tube filled with a mixture of5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one (Intermediate 2, Step A,171 mg, 0.903 mmol), 2-chloro-N,N-dimethylethanamine hydrochloride (130mg, 0.903 mmol) and Cs₂CO₃ (882 mg, 2.71 mmol) was added DMA (1.8 mL).The white suspension was stirred at ambient temperature for 30 minutesand then at 100° C. overnight. The reaction mixture was partitionedbetween water and DCM (20 mL each). The phases were separated, and theaqueous phase was extracted with DCM (2×10 mL). The combined organicphases were washed with brine (3×20 mL), dried (Na₂SO₄), filtered, andconcentrated to a dark brownish oil. The crude was purified by silicachromatography (10-20% MeOH/DCM) to yield the product as beige solid(0.13 g, 51% yield). MS (apci) m/z=261.2 (M+H).

Intermediate Y6

3-(2-(dimethylamino)ethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-amine

To a thick-walled pressure reaction tube filled with a mixture of5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one (Intermediate 2, Step A,171 mg, 0.903 mmol), 2-chloro-N,N-dimethylethanamine hydrochloride (130mg, 0.903 mmol) and Cs₂CO₃ (882 mg, 2.71 mmol) was added DMA (1.8 mL).The white suspension was stirred at ambient temperature for 30 minutesand then at 100° C. overnight. The reaction mixture was partitionedbetween water and DCM (20 mL each). The phases were separated, and theaqueous phase was extracted with DCM (2×10 mL). The combined organicphases were washed with brine (3×20 mL), dried (Na₂SO₄), filtered, andconcentrated to a dark brownish oil. The crude was purified by silicachromatography (10-20% MeOH/DCM) to yield the product as beige solid(0.13 g, 51% yield). MS (apci) m/z=261.2 (M+H).

Intermediate Y7

(R)-tert-butyl2-(((5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)oxy)methyl)morpholine-4-carboxylateStep A: Preparation of (R)-tert-butyl2-(((methylsulfonyl)oxy)methyl)morpholine-4-carboxylate

To a solution of (R)-tert-butyl2-(hydroxymethyl)morpholine-4-carboxylate (2.0 g, 9.205 mmol) and DIEA(2.084 mL, 11.97 mmol) in DCM (46 mL), cooled to 0° C., was added MsCl(0.819 mL, 10.59 mmol). The reaction mixture was allowed to warm slowlyto ambient temperature over 2 hours, then was diluted with H₂O (50 mL),phases separated, and the aqueous phase extracted with DCM (2×25 mL).The combined organic phases were washed with brine (50 mL), dried(MgSO₄), filtered, and concentrated to give the product as a pale yellowoil (3.11 g, 114% yield). ¹H NMR (CDCl₃) δ 4.24 (d, 2H), 3.99-3.80 (m,3H), 3.70 (m, 1H), 3.55 (m, 1H), 3.07 (s, 3H), 2.95 (m, 1H), 2.77 (m,1H), 1.47 (s, 9H).

Step B: Preparation of (R)-tert-butyl2-(((5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)oxy)methyl)morpholine-4-carboxylate

To 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one (Intermediate 2, StepA, 640 mg, 3.386 mmol) were added DMA (7 mL), Cs₂CO₃ (2.21 g, 6.772mmol), and (R)-tert-butyl2-(((methylsulfonyl)oxy)methyl)morpholine-4-carboxylate (1.00 g, 3.386mmol). The mixture was heated in a sealed pressure tube at 110° C. for17 hours, then cooled to ambient temperature. The reaction mixture waspartitioned between water (40 mL) and DCM (40 mL). The phases wereseparated, and the aqueous phase was extracted with DCM (2×25 mL). Thecombined organic phases were washed with brine (3×50 mL), dried (MgSO₄),filtered, and concentrated. The crude oil was purified by silica columnchromatography, eluting with 0-50% acetone/hexanes, to afford theproduct as a thick amber syrup (871 mg, 66% yield). MS (apci) m/z=389.2(M+H).

Intermediate Y8

(R)-tert-butyl2-(((5-amino-1-phenyl-1H-pyrazol-3-yl)oxy)methyl)morpholine-4-carboxylate

Prepared according to the procedure of Intermediate Y7, replacing5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one in Step B with5-amino-1-phenyl-1H-pyrazol-3(2H)-one (Intermediate 203, Step A), toafford the product as a thick amber syrup (489 mg, 39% yield). MS (apci)m/z=375.2 (M+H).

Intermediate Y9

3-(2-(tert-butyldimethylsilyloxy)ethyl)-4-methyl-1-phenyl-1H-pyrazol-5-amine

To a solution of 2-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)ethanol(Intermediate P127, 172 mg, 0.792 mmol) in DMF (1 mL) were addedTBDMS-Cl (263 mg, 1.74 mmol), then imidazole (135 mg, 1.98 mmol). Thereaction mixture was stirred at ambient temperature for 17 hours, thenwas diluted with H₂O (20 mL) and extracted with DCM (3×20 mL). Thecombined organic phases were washed with brine (20 mL), dried (MgSO₄),filtered and concentrated to afford the product as a pale brown syrup(249 mg, 95% yield). MS (apci) m/z=332.2 (M+H).

The table below provides a list of commercially available compounds thatwere used in the synthesis of intermediates and examples.

Structure Vendor/Catalog # CAS #

Alfa Aesar/AAAL11430-06 447-53-0

J & W/20-0827S Not available

CiVenti Chem/CV-1709 166978-46-7

Aldrich/B10587 826-73-3

NOVEL Chemical Solutions/AC0320 Not available

Combi-Blocks, Inc./SS-0260 1170470-60-6

Activate Scientific/AS2100M500 Not available

Combi-Blocks, Inc./SS-0277 Not available

Activate Scientific/AS2096M500 Not available

PREPARATION OF SYNTHETIC EXAMPLES Example 1

1-(1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-yl)-3-(1,2,3,4-tetrahydronaphthalen-1-yl)urea

1,2,3,4-tetrahydronaphthalen-1-amine (59.1 mg, 0.402 mmol), phenyl1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-ylcarbamate (Intermediate13; 100 mg, 0.268 mmol) and DIEA (233 μL, 1.34 mmol) were combined in0.2 mL of DMF and stirred at ambient temperature for 1 hour. The mixturewas loaded onto a samplet and purified by reverse-phase columnchromatography, eluting with 10-80% acetonitrile/water, to afford thetitle compound (71 mg, 0.166 mmol, 62.2% yield). (MS (apci) m/z=427.2(M+H).

The compounds in Table 2 were prepared by reacting the appropriate aminefrom Table 1 with the appropriate intermediate phenylcarbamate using themethod described for Example 1.

TABLE 2 Example MS (apci) # Structure Name m/z 2

(S)-1-(1′,4-dimethyl- 1-phenyl-1H,1′H-3,4′- bipyrazol-5-yl)-3-(1,2,3,4-tetrahydro- naphthalen-1-yl)urea 427.2 (M + H) 3

(S)-1-(2-phenyl- 2,4,5,6-tetrahydro- cyclopenta[c]pyrazol-3-yl)-3-(l,2,3,4-tetra- hydronaphthalen-1- yl)urea 373.2 (M + H) 4

(R)-1-(1′,4-dimethyl- 1-phenyl-1H,1′H-3,4′- bipyrazol-5-yl)-3-(1,2,3,4-tetrahydro- naphthalen-1-yl)urea 427.2 (M + H) 5

1-(1′,4-dimethyl-1- phenyl-1H,1′H-3,4′- bipyrazol-5-yl)-3-(6-methoxy-1,2,3,4- tetrahydronaphthalen- 1-yl)urea 457.2 (M + H) 6

1-(1′,4-dimethyl-1- phenyl-1H,1′H-3,4′- bipyrazol-5-yl)-3-(6,7,8,9-tetrahydro- 5H-benzo[7]annulen- 5-yl)urea 441.2 (M + H) 7

1-(chroman-4-yl)-3- (1′,4-dimethyl-1- phenyl-1H,1′H-3,4′-bipyrazol-5-yl)urea 429.2 (M + H) 8

1-(1′,4-dimethyl-1- phenyl-1H,1′H-3,4′- bipyrazol-5-yl)-3-(isochroman-4-yl)urea 429.2 (M + H) 9

1-(1′,4-dimethyl-1- phenyl-1H,1′H-3,4′- bipyrazol-5-yl)-3-(2,2-dimethyl- chroman-4-yl)urea 457.2 (M + H) 10

1-(6-bromoiso- chroman-4-yl)-3- (1′,4-dimethyl-1- phenyl-1H,1′H-[3,4′-bipyrazol]-5- yl)urea 507.1; 509.1 (M + H)

Example 11

(S)-1-(4-bromo-3-methyl-l-phenyl-1H-pyrazol-5-yl)-3-(1,2,3,4-tetrahydronaphthalen-1-yl)urea

Phenyl (3-methyl-1-phenyl-1H-pyrazol-5-yl)carbamate (Intermediate 1; 40mg, 0.136 mmol) was dissolved in 1 mL of DCM and N-Bromosuccinimide(29.1 mg, 0.164 mmol) was added.(S)-1,2,3,4-tetrahydronaphthalen-1-amine (30.1 mg, 0.205 mmol) was addedfollowed by DIEA (119 μL, 0.682 mmol). The reaction was stirred for 2hours, concentrated and purified by reverse-phase column chromatography,eluting with 0-90% acetonitrile/water, to afford the title compound (56mg, 0.132 mmol, 96.5% yield). (MS (apci) m/z=425.0; 427.0 (M+H).

Example 12

1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(7-fluorochroman-4-yl)urea Step A:Preparation of 7-fluorochroman-4-one oxime

7-fluorochroman-4-one (1.00 g, 6.02 mmol), hydroxylamine hydrochloride(0.627 g, 9.03 mmol) and NaOAc (0.741 g, 9.03 mmol) were combined inEtOH (40 mL) and heated at 100° C. in a sealed vessel overnight. Thereaction was filtered through Celite® to afford the title compound as a0.15M solution in EtOH (40 mL, 6.02 mmol). MS (apci) m/z=182.1 (M+H).

Step B: Preparation of 7-fluorochroman-4-amine

Zn dust (1970 mg, 30.1 mmol) was added to 7-fluorochroman-4-one oxime(solution in EtOH, 20056 μL, 3.01 mmol) and the reaction was stirred atambient temperature for 4 hours. The reaction was filtered throughCelite® and concentrated. The crude product was taken up in 1N HCl (20ml) and washed with EtOAc (40 mL). The aqueous layer was adjusted topH >10 with 2N NaOH and extracted with DCM (2×50 mL). The combined DCMextracts were dried (MgSO₄), filtered and concentrated to provide thetitle compound (488 mg, 2.92 mmol, 97.0% yield). MS (apci) m/z=151.1(M+H—NH₃).

Step C: Preparation of 1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(7-fluorochroman-4-yl)urea

Phenyl (1′,4-dimethyl-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-yl)carbamate(25 mg, 0.0670 mmol), 7-fluorochroman-4-amine (16.8 mg, 0.100 mmol) andDIEA (117 μL, 0.670 mmol) were combined in 0.2 mL of DMF and stirredambient temperature for 1 hour. The mixture was loaded onto a sampletand purified by reverse-phase column chromatography, eluting with 0-70%acetonitrile/water, to afford the title compound (19.5 mg, 0.0437 mmol,65.2% yield). MS (apci) m/z=447.1 (M+H).

The compounds in Table 3 were prepared using the appropriate ketone fromTable 1 according to the method as described for Example 12 and usingthe appropriate intermediate phenylcarbamate in Step C.

TABLE 3 Example MS (apci) # Structure Name m/z 13

1-(3-ethoxy-4- methyl-1-phenyl- 1H-pyrazol-5-yl)- 3-(7-fluoro-chroman-4-yl)urea 411.2 (M + H) 14

1-(1′,4-dimethyl- 1-phenyl-1H,1′H- [3,4′-bipyrazol]-5-yl)-3-(6-fluoro-2- methylchroman-4- yl)urea 461.2 (M + H) 15

1-(7-bromo-1,2,3,4- tetrahydro- naphthalen-1-yl)- 3-(1′,4-dimethyl-1-phenyl-1H,1′H- [3,4′-bipyrazol]-5- yl)urea 503.1; 505.0 (M + H) 16

1-(7-bromo-4,4- dimethyl-1,2,3,4- tetrahydro- naphthalen-1-yl)-3-(1′,4-dimethyl- 1-phenyl-1H,1′H- [3,4′-bipyrazol]- 5-yl)urea 533.1;535.1 (M + H)

Example 17

1-(1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-yl)-3-(3-(2-methoxyethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)ureaStep A: Preparation of 1-(1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-yl)-3-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)urea

1-Amino-4,5-dihydro-1H-benzo[d] azepin-2(3H)-one (260 mg, 1.47 mmol),phenyl 1′,4-dimethyl-1-phenyl-1H, 1′H-3,4′-bipyrazol-5-ylcarbamate(Intermediate 13; 500 mg, 1.34 mmol) and DIEA (1166 μL, 6.70 mmol) werecombined in 0.2 mL of DMF and stirred ambient temperature for 2 hours. Athick white slurry formed. Water (2 mL) was added and the white solidwas collected, washed with water (1 mL) and DCM (2×1 mL) and air-driedto afford the title compound (517 mg, 1.13 mmol, 84.8% yield). MS (apci)m/z=456.2 (M+H).

Step B: Preparation of 1-(1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-yl)-3-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)urea

1-(1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-yl)-3-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)urea(100 mg, 0.2195 mmol) was dissolved in 5 mL of THF and a solution of LAHin THF (548.8 μL, 0.5488 mmol) was added dropwise. The reaction wasstirred at ambient temperature overnight. Additional LAH (548.8 μL,0.5488 mmol) was added and the reaction was stirred at ambienttemperature for 24 hours. Na₂SO₄. (10H₂O) (3537 mg, 10.98 mmol) wasadded and the reaction was stirred for 2 hours, filtered andconcentrated. The crude product was by reverse-phase columnchromatography, eluting with 0-70% acetonitrile/water, to afford thetitle compound (40 mg, 0.09059 mmol, 41.27% yield). MS (apci) m/z=442.2(M+H).

Step C: Preparation of 1-(1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-yl)-3-(3-(2-methoxyethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)urea

1-(1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-yl)-3-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)urea(20.00 mg, 0.04530 mmol), 1-bromo-2-methoxyethane (18.89 mg, 0.1359mmol) and DIEA (39.45 μl, 0.2265 mmol) were combined in 0.2 mL of DMFand stirred at ambient temperature overnight. The mixture was loadedonto a samplet and purified by reverse-phase column chromatography,eluting with 0-70% acetonitrile/water, to afford the title compound (6.3mg, 0.01261 mmol, 27.84% yield). MS (apci) m/z=500.3 (M+H).

The compounds in Table 4 were prepared using the method as described forExample 17, Step C using the electrophile specified instead of1-bromo-2-methoxyethane.

TABLE 4 Ex. MS (apci) # Electrophile Structure Name m/z 18

1-(1′,4-dimethyl- 1-phenyl-1H,1′H- 3,4′-bipyrazol-5- yl)-3-(3-(2,2,2-trifluoroethyl)- 2,3,4,5-tetra- hydro-1H-benzo- [d]azepin-1-yl)- urea522.2 (M − H) 19

1-(3-acetyl- 2,3,4,5-tetrahydro- 1H-benzo[d]- azepin-1-yl)-3-(1′,4-dimethyl-1- phenyl-1H,1′H- 3,4′-bipyrazol-5- yl)urea 482.2 (M − H)20

1-(1′,4-dimethyl- 1-phenyl-1H,1′H- 3,4′-bipyrazol-5- yl)-3-(3-propionyl-2,3,4,5-tetrahydro- 1H-benzo-[d]- azepin-1-yl)urea 498.2 (M + H)

(1-(1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-yl)-3-(3-propyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)urea

1-(1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-yl)-3-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)urea(15.00 mg, 0.03397 mmol), propionaldehyde (9.866 mg, 0.1699 mmol) andNaBH(OAc)₃ (14.40 mg, 0.06795 mmol) were combined in 1 mL of DCM andstirred at ambient temperature for 3 days. Additional NaBH(OAc)₃ (14.40mg, 0.06795 mmol) and 1 mL of THF were added and the reaction wasstirred at ambient temperature overnight. NaOH (1N, 1 mL) and DCM (3 mL)were added and the reaction was agitated and filtered through a PhaseSeparator frit. The organic extract was concentrated and purified byreverse-phase column chromatography, eluting with 0-80%acetonitrile/water, to afford the title compound (1.0 mg, 0.0021 mmol,6.09% yield). (MS (apci) m/z=484.3 (M+H).

Example 22

1-(2-ethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureaStep A: Preparation of2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid

1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (530 mg, 2.99 mmol),Boc₂O (685 mg, 3.14 mmol) and NEt₃ (1251 μl, 8.97 mmol) were combined inDCM (20 mL) and stirred at ambient temperature overnight. The reactionwas poured into 1N HCl (20 mL), the layers were separated and theaqueous layer was extracted with EtOAc (2×25 mL). The combined organicextracts were dried (MgSO₄) and concentrated to provide the titlecompound (830 mg, 2.99 mmol, 100% yield). MS (apci) m/z=178.1 (M+H-Boc).

Step B: Preparation of tert-butyl4-(3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureido)-3,4-dihydroisoquinoline-2(1H)-carboxylate

2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid(325 mg, 1.17 mmol), NEt₃ (490 μL, 3.52 mmol), and diphenylphosphorylazide (379 μL, 1.76 mmol) were combined in 2 mL of Toluene in a pressuretube and stirred at 80° C. for 30 minutes. The reaction was cooled and2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine (304 mg, 1.52mmol) added. The reaction was stirred at 80° C. overnight, cooled,concentrated and purified by reverse-phase column chromatography,eluting with 0-70% acetonitrile/water, to afford the title compound (320mg, 0.676 mmol, 57.7% yield). MS (apci) m/z=474.2 (M+H).

Step C: Preparation of1-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-3-(1,2,3,4-tetrahydroisoquinolin-4-yl)ureahydrochloride

Tert-butyl4-(3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureido)-3,4-dihydroisoquinoline-2(1H)-carboxylate(400 mg, 0.845 mmol) and HCl in IPA (507 μL, 2.53 mmol) were combined in2 mL of DCM and stirred ambient temperature for 3 days. The mixture wasconcentrated to afford the title compound (320 mg, 0.781 mmol, 92.4%yield). MS (apci) m/z=374.2 (M+H).

Step D: Preparation of1-(2-ethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

1-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-3-(1,2,3,4-tetrahydroisoquinolin-4-yl)ureahydrochloride (15 mg, 0.037 mmol), iodoethane (17 mg, 0.11 mmol) andDIEA (32 μL, 0.18 mmol) were combined in 0.2 mL of DMF and stirredambient temperature overnight. The mixture was loaded onto a samplet andpurified by reverse-phase column chromatography, eluting with 0-70%acetonitrile/water, to afford the title compound (4.0 mg, 0.0100 mmol,27% yield. MS (apci) m/z=402.2 (M+H).

Example 23

1-(2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinolin-4-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

Prepared by the method as described in Example 28, step D using1-bromo-2-methoxyethane instead of iodoethane. The material was purifiedby reverse-phase column chromatography using 0-60% acetonitrile/H₂O asthe eluent to provide the title compound (10.1 mg, 0.0234 mmol, 64.0%yield). MS (apci) m/z=432.2 (M+H).

Example 24

1-(2-acetyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

1-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-3-(1,2,3,4-tetrahydroisoquinolin-4-yl)ureahydrochloride (20 mg, 0.049 mmol), Ac₂O (7.58 μL, 0.0803 mmol) and NEt₃(7.46 μL, 0.0536 mmol) were combined in 2 mL of DCM and stirred ambienttemperature for 1 hour. NaOH (1N, 3 mL) was added and the reaction wasextracted with several portions of DCM in a phase separator frit andconcentrated to provide the title compound (18.6 mg, 0.0448 mmol, 91.8%yield). MS (apci) m/z=416.2 (M+H).

Example 25

1-(1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-yl)-3-(2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-4-yl)ureaStep A: Preparation of2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-4-amine

1,2,3,4-tetrahydroisoquinolin-4-amine dihydrochloride (660 mg, 2.98mmol) was suspended in DMF (5 mL) and NEt₃ (437 μL, 3.13 mmol) added.The mixture was stirred for 4 hours and 2,2,2-trifluoroethyltrifluoromethanesulfonate (693 mg, 2.98 mmol) added. The mixture wasstirred for 4 days, quenched with aqueous NaOH (4477 μL, 8.95 mmol) andextracted with several portions of EtOAc. The combined organic extractswere filtered through phase separator paper, concentrated and purifiedby reverse-phase column chromatography, eluting with 0-60%acetonitrile/water, to afford the title compound(2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-4-amine (195 mg,0.847 mmol, 28.4% yield). 1H NMR (CDCl₃) 7.32-7.39 (m, 1H), 7.15-7.26(m, 2H), 7.00-7.06 (m, 1H), 3.91-4.04 (m, 2H), 3.78 (d, J=15 Hz, 1H),3.14-3.25 (m, 2H), 2.91-3.09 (m, 2H), 1.71 (bs, 2H) ppm.

Step B: Preparation of 1-(1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-yl)-3-(2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-4-yl)urea

2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-4-amine (19 mg,0.0825 mmol), phenyl 1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-ylcarbamate (Intermediate 13; 28.0 mg, 0.0750 mmol)and NEt₃ (31.4 μL, 0.225 mmol) were combined in 0.2 mL of DMF andstirred ambient temperature for 2 hours. The mixture was loaded onto asamplet and purified by reverse-phase column chromatography, elutingwith 10-80% acetonitrile/water, to afford the title compound (27.7 mg,0.0544 mmol, 72.5% yield). MS (apci) m/z=510.2 (M+H).

The compounds in Table 5 were prepared using the method described forExample 25, Step C, using the appropriate intermediate phenylcarbamateinstead of phenyl 1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-ylcarbamate.

TABLE 5 Ex. MS (apci) # Structure Name m/z 26

1-(4-methyl-3-(1- methyl-6-oxo-1,6- dihydropyridin-3- yl)-1-phenyl-1H-pyrazol-5-yl)-3- (2-(2,2,2-trifluoro- ethyl)-1,2,3,4- tetrahydroiso-quinolin-4-yl)urea 535.2 (M + H) 27

1-(4-methyl-3-(1- methyl-1H- imidazol-4-yl)-1- phenyl-1H-pyrazol-5-yl)-3-(2-(2,2,2- trifluoroethyl)- 1,2,3,4-tetrahydro-isoquinolin-4-yl)- urea 510.2 (M + H) 28

1-(2-phenyl- 2,4,5,6-tetrahydro- cyclopenta[c]- pyrazol-3-yl)-3-(2-(2,2,2-trifluoro- ethyl)-1,2,3,4- tetrahydroiso- quinolin-4-yl)urea456.2 (M + H) 29

N,4-dimethyl-1- phenyl-5-(3-(2- (2,2,2-trifluoro- ethyl)-1,2,3,4-tetrahydroiso- quinolin-4-yl)- ureido)-1H- pyrazole-3- carboxamide 485.2(M + H)

Example 30

1-(4-methyl-5-oxo-2-phenyl-2,5-dihydro-1H-pyrazol-3-yl)-3-(2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-4-yl)urea

CDI (360 mg, 2.22 mmol), 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one(350 mg, 1.85 mmol) and DIEA (805 μL, 4.62 mmol) were combined in 3 mLof DMF and stirred at ambient temperature overnight. Additional CDI (360mg, 2.22 mmol) was added and the reaction stirred for 24 hours. Aportion of the reaction mixture (365 μL; 0.182 mmol) was combined withNEt₃ (63.6 μL, 0.456 mmol) and2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-4-amine (35 mg,0.152 mmol) in 0.1 mL of DMF, and the mixture was stirred ambienttemperature for 2 hours. The mixture was loaded onto a samplet andpurified by reverse-phase column chromatography using 0-60%acetonitrile/H₂O as the eluent to provide the title compound (59 mg,0.132 mmol, 87.1% yield). MS (apci) m/z=446.2 (M+H).

Example 31

3-methyl-1-phenyl-5-(3-(2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-4-yl)ureido)-1H-pyrazole-4-carboxamideStep A: Preparation of1-(4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-4-yl)urea

5-amino-3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile (23.7 mg, 0.119mmol), CDI (22.9 mg, 0.141 mmol) and NEt₃ (45.4 μL, 0.326 mmol) werecombined in 0.2 mL of DMF and stirred ambient temperature overnight.2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-4-amine (25 mg,0.109 mmol) was added and the reaction was stirred at ambienttemperature for 2 hours. The mixture was loaded onto a samplet andpurified by reverse-phase column chromatography using 0-80%acetonitrile/H₂O as the eluent to afford the title compound (38 mg,0.084 mmol, 77.0% yield), which was used immediately in the next step.MS (apci) m/z=453.2 (M−H).

Step B: Preparation of3-methyl-1-phenyl-5-(3-(2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-4-yl)ureido)-1H-pyrazole-4-carboxamide

1-(4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-4-yl)urea(35 mg, 0.07702 mmol), and aqueous concentrated HCl (390.01 mg, 3.8508mmol) were combined and stirred at ambient temperature for 5 days. Thereaction was poured into NaOH (aqueous, 3850.8 μL, 7.702 mmol) and ice(2 g) and extracted with several portions of 10% IPA/DCM in a phaseseparator frit. The combined organic extracts were concentrated andpurified by reverse-phase column chromatography using 0-80%acetonitrile/H₂O as the eluent to provide the title compound (5.3 mg,0.0112 mmol, 14.6% yield). MS (apci) m/z=471.2 (M−H).

Example 32

1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(6-(methoxymethyl)isochroman-4-yl)urea

Potassium methoxymethyltrifluoroborate (12 mg, 0.079 mmol),1-(6-bromoisochroman-4-yl)-3-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea (20 mg, 0.039 mmol),Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (6.4 mg, 0.0079 mmol) and Cs₂CO₃ (64 mg, 0.20mmol) were combined in dioxane (2 mL) and water (0.5 mL) in a pressuretube and degassed by bubbling N₂ through the mixture for 10 minutes. Thereaction was sealed and heated at 100° C. for 16 hours, cooled, pouredinto brine (10 mL), and extracted with EtOAc (2×10 mL). The combinedorganic extracts were concentrated and purified by reverse-phase columnchromatography using 0-70% acetonitrile/H₂O as the eluent to provide thetitle compound (9.8 mg, 0.021 mmol, 53% yield). MS (apci) m/z=473.2(M+H).

Example 33

1-(6-bromo-2-cyclopropylchroman-4-yl)-3-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)ureaStep A: Preparation of 6-bromo-2-cyclopropylchroman-4-one

1-(5-bromo-2-hydroxyphenyl)ethanone (2.0 g, 9.3 mmol),cyclopropanecarbaldehyde (0.78 g, 11 mmol), and pyrrolidine (0.78 mL,9.3 mmol) were combined in CH₃CN (20 mL), and stirred at ambienttemperature for 18 hours. The mixture was concentrated and diluted withdiethyl ether (50 mL) and aqueous 1N HCl (20 mL). The phases wereseparated and the organic phase was washed with aqueous 1N NaOH (20 mL),then brine (200 mL), dried (MgSO₄), filtered, and concentrated. Thecrude product was purified by silica gel column chromatography using5-20% EtOAc/hexanes as the eluent to afford the title compound (1.7 g,6.4 mmol, 68% yield). MS (apci) m/z=264.9; 266.9 (M−H).

Step B: Preparation of1-(6-bromo-2-cyclopropylchroman-4-yl)-3-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea

Prepared using 6-bromo-2-cyclopropylchroman-4-one according to theprocedure described in Example 12, Steps A-C. The final compound waspurified by reverse-phase column chromatography using 0-80%acetonitrile/H₂O as the eluent to provide the title compound as amixture of diastereomers (85 mg, 0.1553 mmol, 23.8% yield for threesteps). MS (apci) m/z=545.1; 547.2 (M−H).

Example 34

1-(6-bromospiro[chroman-2,1′-cyclobutan]-4-yl)-3-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea Step A: Preparation of6-bromospiro[chroman-2,1′-cyclobutan]-4-one

A solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (20 g, 93.00 mmol),cyclobutanone (27.80 mL, 372.0 mmol) and pyrrolidine (8.540 mL, 102.3mmol) in toluene (150 mL, 93.00 mmol) was heated at reflux overnight.The reaction was partitioned between EtOAc and 2 N HCl, the aqueouslayer was washed with EtOAc, and the combined organic extracts werewashed with brine, dried (Na₂SO₄) and concentrated. The crude productwas purified by silica gel column chromatography using 1-15%EtOAc/hexanes as the eluent to afford the title compound (14.04 g, 52.56mmol, 56.5% yield) as a yellow solid. MS (apci) m/z=266.0; 268.0 (M+).

Step B: Preparation1-(6-bromospiro[chroman-2,1′-cyclobutan]-4-yl)-3-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea

Prepared from 6-bromo-2-cyclopropylchroman-4-one according to theprocedure described in Example 12, Steps A-C. The final compound waspurified by reverse-phase column chromatography using 0-80%acetonitrile/H₂O as the eluent to provide the title compound (99 mg,0.1808 mmol, 20.0% yield for three steps). MS (apci) m/z=545.2; 547.2(M−H).

Example 35A and 35B

1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(6-(methoxymethyl)spiro[chroman-2,1′-cyclobutan]-4-yl)ureaand

1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(spiro[chroman-2,1′-cyclobutan]-4-yl)urea

Potassium methoxymethyltrifluoroborate (18 mg, 0.12 mmol),1-(6-bromospiro[chroman-2,1′-cyclobutan]-4-yl)-3-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea (Example 34; 33 mg, 0.060 mmol),dichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium (II)dichloromethane adduct (9.8 mg, 0.012 mmol) and Cs₂CO₃ (98 mg, 0.30mmol) were combined in dioxane (2 mL) and water (0.5 mL) and degassed bybubbling N2 through the mixture for 10 minutes. The reaction was thensealed in a glass tube and heated at 100° C. for 3 hours. The reactionwas cooled, poured into brine (10 mL) and extracted with EtOAc (2×10mL). The combined organic extracts were concentrated and purified byreverse-phase column chromatography using 0-70% acetonitrile/H₂O as theeluent to provide the title compounds: 1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(6-(methoxymethyl)spiro[chroman-2,1′-cyclobutan]-4-yl)urea[second peak, 2.8 mg, 0.0055 mmol, 9.1% yield, MS (apci) m/z=513.3(M+H)] and1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(spiro[chroman-2,1′-cyclobutan]-4-yl)urea[first peak, 2.50 mg, 0.0053 mmol, 8.8% yield, MS (apci) m/z=469.2(M+H)].

Example 36

1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(4-oxo-1,2,3,4-tetrahydronaphthalen-1-yl)urea

4-Oxo-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (50 mg, 0.263mmol), 1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-amine(Intermediate 12; 66.6 mg, 0.263 mmol), NEt₃ (110 μL, 0.789 mmol) anddiphenylphosphoryl azide (85.0 μL, 0.394 mmol) were combined in 2 mL oftoluene in a sealed pressure tube and stirred at 80° C. overnight. Thereaction was cooled, concentrated and purified by reverse-phase columnchromatography using 0-60% acetonitrile/H₂O as the eluent to provide thetitle compound (68 mg, 0.154 mmol, 58.7% yield). MS (apci) m/z=441.2(M+H).

Example 37

1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(4-hydroxy-4-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)urea

1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(4-oxo-1,2,3,4-tetrahydronaphthalen-1-yl)urea(20 mg, 0.0454 mmol) was dissolved in 5 mL of THF and the solutioncooled to 0° C. MeMgBr in THF (81.1 μL, 0.114 mmol) was added and thereaction was allowed to warm to ambient temperature over 2 hours.Additional MeMgBr in THF (81.1 μL, 0.114 mmol) was added and thereaction stirred at ambient temperature for 1 hours. The reaction wasquenched with water and extracted with several portions of EtOAc. Thecombined organic extracts were filtered through phase separator paper,concentrated and purified by silica gel column chromatography using5-100% acetone/hexanes as the eluent to afford the title compound (4.4mg, 0.00964 mmol, 21.2% yield). MS (apci) m/z=457.2 (M+H).

Example 38

1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(1-oxo-2-(2,2,2-trifluoroethyl)-1,2-dihydroisoquinolin-4-yl)ureaStep A: Preparation of4-nitro-2-(2,2,2-trifluoroethyl)isoquinolin-1(2H)-one

4-Nitroisoquinolin-1(2H)-one (50 mg, 0.26 mmol), 2,2,2-trifluoroethyltrifluoromethanesulfonate (79 mg, 0.34 mmol) and K₂CO₃ (182 mg, 1.3mmol) were combined in 0.2 mL of DMF and stirred at ambient temperaturefor 2 hours. The mixture was filtered, loaded onto a samplet, andpurified by reverse-phase column chromatography eluting with 0-80%acetonitrile/water to afford the title compound (63 mg, 0.23 mmol, 88%yield) as a white solid. ¹H NMR (CDCl₃) 8.66-8.71 (m, 1H), 8.57 (s, 1H),8.49-8.54 (m, 1H), 7.87-7.94 (m, 1H), 7.66-7.72 (m, 1H), 4.73-4.82 (m,2H).

Step B: Preparation of4-amino-2-(2,2,2-trifluoroethyl)isoquinolin-1(2H)-one

4-nitro-2-(2,2,2-trifluoroethyl)isoquinolin-1(2H)-one (5.00 mg, 0.0184mmol) was dissolved in MeOH (0.5 mL) and aqueous saturated NH₄Cl (0.2mL) was added followed by Zn dust (6.01 mg, 0.0919 mmol). The reactionwas stirred at ambient temperature overnight, filtered, and extractedwith several portions of DCM in a phase separator frit. The combined DCMextracts were concentrated to provide the title compound (4.00 mg,0.0165 mmol, 89.9% yield). MS (apci) m/z=243.1 (M+H).

Step C: Preparation of 1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(1-oxo-2-(2,2,2-trifluoroethyl)-1,2-dihydroisoquinolin-4-yl)urea

4-Amino-2-(2,2,2-trifluoroethyl)isoquinolin-1(2H)-one (2.60 mg, 0.0107mmol), phenyl(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)carbamate (4.01 mg,0.0107 mmol) and NEt₃ (4.49 μL, 0.0322 mmol) were combined in 0.2 mL ofDMF and stirred at ambient temperature for 2 hours. The mixture wasloaded onto a samplet and purified by reverse-phase columnchromatography, eluting with 0-70% acetonitrile/water, to afford thetitle compound (2.63 mg, 0.00504 mmol, 47.0% yield). MS (apci) m/z=522.2(M+H).

Example 39

1-(3-methoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-(1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)ureaStep A: Preparation of tert-butyl(1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a solution of tert-butyl (1,2,3,4-tetrahydroquinolin-4-yl)carbamate(250 mg, 1.01 mmol) and DIEA (526 μL, 3.02 mmol) in dry DMF (2.0 mL) wasadded methyl iodide (66.1 μL, 1.06 mmol). The mixture was stirred atambient temperature for 7 hours. Additional methyl iodide (33 μL) wasadded and the mixture was stirred for an additional 16 hours. Themixture was diluted with H₂O (6 mL) and extracted with Et₂O (3×). Thecombined extracts were washed with H₂O (2×) and Brine, dried (MgSO₄) andfiltered through a SiO₂ plug (Et₂O elution). The eluent was concentratedand the residual colorless syrup was purified on a SiO₂ column (CH₂Cl₂elution) to provide the title compound as a colorless film (150 mg, 57%yield). ¹H NMR (CDCl₃) δ 7.16 (dd, J=18.4, 8.7 Hz, 2H), 6.66 (t, J=7.4Hz, 1H), 6.61 (d, J=8.3 Hz, 1H), 4.78 (br s, 1H), 4.74 (br s, 1H), 3.21(t, J=5.7 Hz, 2H), 2.90 (s, 3H), 2.06, (m, 2H), 1.47 (s, 9H) ppm.

Step B: Preparation of 1-methyl-1,2,3,4-tetrahydroquinolin-4-aminedihydrochloride

To a solution of tert-butyl(1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate (145 mg, 0.553 mmol)in EtOAc (4 mL) was added 4M HCl (2.07 mL, 8.29 mmol) in dioxane and themixture was stirred at ambient temperature for 2.5 hours. The resultingwhite suspension was diluted with Et₂O (6 mL) and the solid collectedvia vacuum filtration. The solid was washed with Et₂O and dried undervacuum to afford the title compound as a white solid (100 mg, 77%yield). ¹H NMR (CD₃OD) δ 7.47-7.38 (m, 2H), 7.18-7.05 (m, 2H), 4.62(unresolved, 1H), 3.60-3.48 (m, 2H), 3.13 (s, 3H), 2.51-2.41 (m, 1H),2.33-2.24 (m, 1H) ppm.

Step C: Preparation of1-(3-methoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-(1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)urea

To a mixture of phenyl(3-methoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)carbamate (32.3 mg, 0.100mmol) and 1-methyl-1,2,3,4-tetrahydroquinolin-4-amine dihydrochloride(28.2 mg, 0.120 mmol) in dry CH₂Cl₂ (0.4 mL) was added DIEA (69.7 μL,0.400 mmol) and the resulting solution was stirred at ambienttemperature for 5 hours. The reaction mixture was diluted with CH₂Cl₂ (3mL) and washed sequentially with H₂O, 1M NaOH (2×) and H₂O. The organicphase was dried (Na₂SO₄) and passed through a short SiO₂ column elutingwith CH₂Cl₂, then 50% EtOAc-hexanes. The 50% EtOAc-hexanes pool wasconcentrated and the residual white solid was dried under vacuum toprovide the title compound (34 mg, 87% yield). ¹H NMR (DMSO₆) δ 7.81 (s,1H), 7.49 (d, J=8.3 Hz, 2H), 7.43 (t, J=7.3 Hz, 2H), 7.26 (t, J=7.3 Hz,1H), 7.07 (t, J=7.4 Hz, 1H), 6.97 (d, J=8.2 Hz, 1H), 6.66 (d, J=8.2 Hz,1H), 6.59 (app. dd, J=12.8, 7.4 Hz, 2H), 4.71 (dd, J=13.5, 5.6 Hz, 1H),3.86 (s, 3H), 3.23-3.10 (m, 2H), 2.83 (s, 3H), 1.94-1.81 (m, 2H), 1.78(s, 3H) ppm.

Example 40

1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)urea

To a mixture of phenyl (1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)carbamate (Intermediate 13; 37.3 mg, 0.100mmol) and 1-methyl-1,2,3,4-tetrahydroquinolin-4-amine dihydrochloride(28.2 mg, 0.120 mmol) in dry CH₂Cl₂ (0.4 mL) was added DIEA (69.7 μL,0.400 mmol) and the resulting solution was stirred at ambienttemperature for 5 hours. The reaction mixture was diluted with CH₂Cl₂ (3mL) and washed sequentially with H₂O, 1M NaOH (2×) and H₂O. The organicphase was dried (Na₂SO₄) and passed through a short SiO₂ column elutingwith CH₂Cl₂, 50% EtOAc-hexanes, then EtOAc. The EtOAc pool wasconcentrated and the residual white solid dried under vacuum to furnishthe title compound (42 mg, 95% yield). MS (apci) m/z=442.2 (M+H).

Example 41

1-(1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-3-(4-methyl-3-(1-methyl-6-oxo-1.,6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)urea

To a mixture of phenyl(4-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)carbamate(Intermediate 8; 20.0 mg, 0.050 mmol) and1-methyl-1,2,3,4-tetrahydroquinolin-4-amine dihydrochloride (14.1 mg,0.060 mmol) in dry CH₂Cl₂ (0.4 mL) was added DIEA (34.8 μL, 0.200 mmol)and the resulting solution was stirred at ambient temperature for 4.5hours. The reaction mixture was diluted with CH₂Cl₂ (2 mL) and washedsequentially with H₂O, 1M NaOH (2×) and H₂O. The organic phase was dried(Na₂SO₄) and passed through a short SiO₂ column eluting with CH₂Cl₂,EtOAc then 5% MeOH/EtOAc. The 5% MeOH/EtOAc pool was concentrated andthe residual solid washed with Et₂O and dried under vacuum to furnishthe title compound as a white solid (17 mg, 73% yield). MS (apci)m/z=467.2 (M−H).

Example 42

1-(1-ethyl-1,2,3,4-tetrahydroquinolin-4-yl)-3-(4-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)ureaStep A: Preparation of tert-butyl(1-ethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a solution of tert-butyl (1,2,3,4-tetrahydroquinolin-4-yl)carbamate(250 mg, 1.01 mmol) and DIEA (526 μL, 3.02 mmol) in dry DMF (2.0 mL) wasadded ethyl iodide (121 μL, 1.50 mmol) and the mixture was stirred atambient temperature for 5 hours. The mixture was heated at 50° C. for 16hours and additional ethyl iodide (50.0 μL was added. The mixture washeated at 70° C. for 5 hours and was cooled to ambient temperature. Themixture was diluted with H₂O (12 mL) and extracted with Et₂O (3×). Thecombined extracts were washed with H₂O (2×) and Brine, dried (MgSO₄) andfiltered through a SiO₂ plug (Et₂O elution). The eluent was concentratedand the residual colorless syrup was dried under vacuum to provide thetitle compound (264 mg, 95% yield). ¹H NMR (CDCl₃) δ 7.17 (d, J=7.5 Hz,1H), 7.12 (t, J=7.6 Hz, 1H), 6.61 (t, J=7.5 Hz, 2H), 4.73 (unresolved,2H), 3.44-3.28 (m, 2H), 3.28-3.17 (m, 2H), 2.06-1.99, (m, 2H), 1.47 (s,9H), 1.13 (t, J=7.1 Hz, 3H) ppm.

Step B: Preparation of 1-ethyl-1,2,3,4-tetrahydroquinolin-4-aminedihydrochloride

To a solution of tert-butyl(1-ethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate (264 mg, 0.955 mmol)in EtOAc (3 mL) was added 4M HCl (3.58 mL, 14.3 mmol) in dioxane and themixture was stirred at ambient temperature for 2 hours. The resultingwhite suspension was diluted with Et₂O (8 mL) and the solid collectedvia vacuum filtration. The solid was washed with Et₂O and dried undervacuum to afford the title compound as a white solid (222 mg, 93%yield). ¹H NMR (CD₃OD) δ 7.68-7.59 (m, 1H), 7.57-7.50 (m, 1H), 7.47-7.36(m, 2H), 4.78-4.72 (m, 1H), 3.80-3.60 (m, 4H), 2.67-2.56 (m, 1H),2.41-2.30 (m, 1H), 1.40 (m, 3H) ppm.

Step C: Preparation of1-(1-ethyl-1,2,3,4-tetrahydroquinolin-4-yl)-3-(4-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)urea

The title compound was prepared utilizing1-ethyl-1,2,3,4-tetrahydroquinolin-4-amine dihydrochloride instead of1-methyl-1,2,3,4-tetrahydroquinolin-4-amine dihydrochloride according tothe procedure describe in Example 41. The compound was isolated as awhite solid (25.0 mg, 83% yield). MS (apci) m/z=483.2 (M+H).

Example 43

1-(8-fluoro-1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-3-(4-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)ureaStep A: Preparation of 8-fluoro-2,3-dihydroquinolin-4(1H)-one oxime

To a mixture of 8-fluoro-2,3-dihydroquinolin-4(1H)-one (300 mg, 1.82mmol) and hydroxylamine hydrochloride (379 mg, 5.45 mmol) in absoluteEtOH (18 mL) was added pyridine (294 μL, 3.63 mmol) and the mixture washeated at reflux for 16 hours. The mixture was cooled to ambienttemperature and concentrated. The residual oily solid was treated withH₂O and the mixture extracted with CH₂Cl₂ (3×). The combined organicextracts were washed with H₂O, dried over Na₂SO₄ and passed through aSiO₂ plug (eluting with CH₂Cl₂ and then 25% EtOAc-hexanes for elution).The eluent was concentrated to give a cloudy film that was washed withhexanes and dried under vacuum to provide the title compound as a whitesolid (245 mg, 75% yield). MS (apci) m/z=181.1 (M+H).

Step B: Preparation of 8-fluoro-1,2,3,4-tetrahydroquinolin-4-amine

A solution of 8-fluoro-2,3-dihydroquinolin-4(1H)-one oxime (225 mg, 1.25mmol) in MeOH (5 mL) was cooled to 0° C. and Zn dust (<10 micron, 408.2mg, 6.24 mmol) was added in one portion. Saturated NH₄Cl (1.0 mL) wasadded over 2 minutes and the mixture was stirred for 5 minutes. Themixture was allowed to reach ambient temperature and was stirred for 6hours. The mixture was filtered through packed Celite® (MeOH for rinseand elution) and concentrated to a colorless syrup. The syrup wastreated with 1M K₂CO₃ (5 mL) and extracted with EtOAc (3×). The combinedextracts were dried over MgSO₄, filtered through packed Celite® andconcentrated to provide the title compound as a colorless syrup that wasdried under vacuum (183 mg, 88% yield). ¹H NMR (CDCl₃) δ 6.99 (d, J=7.4Hz, 1H), 6.84 (dd, J=11.3, 8.0 Hz, 1H), 6.56 (app dt, J=8.0, 5.2 Hz,1H), 4.14 (br s, 1H), 4.03 (t, J=4.8 Hz, 1H), 3.46-3.33 (m, 2H),2.06-1.98 (m, 1H), 1.88-1.81 (m, 1H), 1.56 (br s, 2H) ppm.

Step C: Preparation of tert-butyl(8-fluoro-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

A solution of 8-fluoro-1,2,3,4-tetrahydroquinolin-4-amine (180 mg, 1.08mmol) in THF (3 mL) was cooled to 0° C. and Boc₂O (244 mg, 1.08 mmol)was added in one portion. The mixture was stirred for 15 minutes then atambient temperature for 2 hours. The mixture was concentrated to acolorless syrup that was dried under vacuum for 16 hours. The syrup wasdissolved in Et₂O and eluted through a SiO₂ plug eluting with Et₂O. Theeluent was concentrated and the residual colorless film was dried undervacuum to provide the title compound as a white foam (289 mg, 100%yield). ¹H NMR (CDCl₃) δ 6.98 (d, J=7.7 Hz, 1H), 6.86 (dd, J=11.0, 8.0Hz, 1H), 6.56 (app dt, J=7.9, 5.3 Hz, 1H), 4.84 (unresolved, 1H), 4.74(unresolved, 1H), 4.13 (br s, 1H), 3.43-3.36 (m, 1H), 3.34-2.26 (m, 1H),2.05 (q, J=5.4 Hz, 2H), 1.47 (s, 9H) ppm.

Step D: Preparation of tert-butyl(8-fluoro-1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a solution of tert-butyl(8-fluoro-1,2,3,4-tetrahydroquinolin-4-yl)carbamate (288 mg, 1.08 mmol)and DIEA (565 μL, 3.24 mmol) in dry DMA (4 mL) was added methyl iodide(101 μL, 1.62 mmol) and the mixture stirred at ambient temperature for 5hours. Additional methyl iodide (101 μL, 1.62 mmol) was added and themixture heated at 50° C. for 6 hours. The reaction mixture was cooled toambient temperature and was diluted with H₂O (25 mL). The mixture wasextracted with Et₂O (3×) and the combined organic extracts were washedwith H₂O (2×) and saturated NaCl. The organic portion was dried overMgSO₄/activated carbon and eluted through a SiO₂ plug (Et₂O elution).The eluent was concentrated to provide the title compound as a whitesolid after drying under vacuum (100 mg, 33% yield). ¹H NMR (CDCl₃) δ7.00 (d, J=7.7 Hz, 1H), 6.89 (dd, J=11.0, 8.0 Hz, 1H), 6.68 (app dt,J=7.9, 5.3 Hz, 1H), 4.84 (unresolved, 1H), 4.74 (br s, 2H), 3.18-3.08(m, 2H), 2.98 (s, 3H), 2.06-1.95 (m, 2H), 1.47 (s, 9H) ppm.

Step E: Preparation of8-fluoro-1-methyl-1,2,3,4-tetrahydroquinolin-4-amine dihydrochloride

To a solution of tert-butyl(8-fluoro-1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate (45.0 mg,0.161 mmol) in EtOAc (0.6 mL) was added 4M HCl (602 μL, 2.41 mmol) indioxane and the mixture was stirred at ambient temperature for 3 hours.The resulting white suspension was diluted with Et₂O (5 mL) and thesolid collected via vacuum filtration. The solid was washed with Et₂Oand dried under vacuum to afford the title compound as an ivory whitesolid (39 mg, 96% yield). MS (apci) m/z=181.1 (M+H).

Step F:1-(8-fluoro-1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-3-(4-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)urea

The title compound was prepared utilizing8-fluoro-1-methyl-1,2,3,4-tetrahydroquinolin-4-amine dihydrochlorideinstead of 1-methyl-1,2,3,4-tetrahydroquinolin-4-amine dihydrochloridein the preparation outlined for Example 41. The compound was isolated asa white solid (18 mg, 59% yield). MS (apci) m/z=487.2 (M+H).

Example 44

1-(6-chloro-8-fluoro-1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-3-(4-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)ureaStep A: Preparation of tert-butyl(6-chloro-8-fluoro-1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

A solution of tert-butyl(8-fluoro-1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate (45.0 mg,0.160 mmol) in CH₃CN (1.6 mL) was cooled to 0° C. andN-chlorosuccinimide (23.6 mg, 0.177 mmol) was added in one portion. Themixture was stirred for 4 hours during which time the temperature roseto ambient after 1 hour. The mixture was treated with pyridin-1-ium4-methylbenzenesulfonate (PPTS) (4.03 mg, 0.016 mmol) and was heated at45° C. for 20 hours. The reaction mixture was added to half-saturatedNaHCO₃ (4 mL) and mixed. The mixture was extracted with CH₂Cl₂ (3×) andthe combined extracts washed with H₂O (2×) and dried overNa₂SO₄/activated carbon. The dried solution was filtered through a SiO₂plug (CH₂Cl₂ elution) and concentrated. The residue was dried undervacuum to afford the title compound as a light yellow solid (30 mg, 59%yield). MS (apci) m/z=315.1 (M+H).

Step B: Preparation of6-chloro-8-fluoro-1-methyl-1,2,3,4-tetrahydroquinolin-4-aminedihydrochloride

To a solution of tert-butyl(6-chloro-8-fluoro-1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(29.0 mg, 0.083 mmol) in EtOAc (1.0 mL) was added 4M HCl (1.04 μL, 4.15mmol) in dioxane and the mixture was stirred at ambient temperature for16 hours. The resulting white suspension was diluted with Et₂O (5 mL)and the solid collected via vacuum filtration. The solid was washed withEt₂O and dried under vacuum to afford the title compound as a whitesolid (18 mg, 75% yield). ¹H NMR (CD₃OD) δ 7.19-7.14 (m, 2H), 4.51 (m,1H), 3.31 (s, 3H), 3.10-3.08 (m, 2H), 2.29-2.19 (m, 1H), 2.18-2.09 (m,1H) ppm.

Step C: Preparation of1-(6-chloro-8-fluoro-1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-3-(4-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)urea

Prepared according to the method of Example 41, using6-chloro-8-fluoro-1-methyl-1,2,3,4-tetrahydroquinolin-4-aminedihydrochloride instead of 1-methyl-1,2,3,4-tetrahydroquinolin-4-aminedihydrochloride. The title compound was obtained as a white solid (16mg, 56% yield). MS (apci) m/z=519.2 (M−H).

Example 45

1-(6-chloro-1-ethyl-1,2,3,4-tetrahydroquinolin-4-yl)-3-(4-methyl-3-(1-methyl-6-oxo-6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)ureaStep A: Preparation of tert-butyl(6-chloro-1-ethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

A solution of tert-butyl(1-ethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate (165 mg, 0.597 mmol)in dry CH₃CN (3 mL) was cooled to 0° C. and N-chlorosuccinimide (85.4mg, 0.627 mmol) was added in one portion. The mixture was stirred for 6hours during which time the temperature rose to ambient after 1 hour.The reaction mixture was treated with saturated NaHCO₃ (4 mL) and H₂O (4mL) and mixed. The mixture was extracted with Et₂O (3×) and the combinedextracts were washed with H₂O (2×), saturated NaCl and dried overMgSO₄/activated carbon. The dried solution was filtered through a SiO₂plug (Et₂O elution) and concentrated. The residue was purified on a SiO₂column (25%, 50%, 100% CH₂Cl₂-hexanes step gradient) to provide thetitle compound as a white solid (70 mg, 38% yield). ¹H NMR (CDCl₃) δ7.13 (s, 1H), 7.05 (d, J=8.8 Hz, 1H), 6.52 (d, J=8.8 Hz, 1H), 4.70(unresolved, 2H), 3.42-3.24 (m, 2H), 3.23 (dd, J=5.4, 5.4 Hz, 2H), 2.01(dd, J=10.6, 4.7 Hz, 2H), 1.48 (s, 9H), 1.12 (t, J=7.1 Hz, 3H) ppm.

Step B: Preparation of6-chloro-1-ethyl-1,2,3,4-tetrahydroquinolin-4-amine dihydrochloride

To a solution of tert-butyl(6-chloro-1-ethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate (69.0 mg,0.220 mmol) in dry EtOAc (2.0 mL) was added 4M HCl (1.67 mL, 6.68 mmol)in dioxane and the mixture was stirred at ambient temperature for 4hours. The mixture was treated with additional 4M HCl (1.67 mL, 6.68mmol) in dioxane and MeOH (0.5 mL) and stirred for 1 hour. The mixturewas concentrated to a clear glass that was treated with Et₂O andagitated until fine white suspension formed. The solid was allowed tosettle, the solvent decanted and the residual solid washed with Et₂O(2×). The solid was dried under vacuum to furnish the title compound asa white solid (56 mg, 89% yield). MS (apci) m/z=194.1 (M-NH₂).

Step C: Preparation of1-(6-chloro-1-ethyl-1,2,3,4-tetrahydroquinolin-4-yl)-3-(4-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)urea

The title compound was prepared utilizing6-chloro-1-ethyl-1,2,3,4-tetrahydroquinolin-4-amine dihydrochlorideinstead of 1-methyl-1,2,3,4-tetrahydroquinolin-4-amine dihydrochloridein the preparation outlined for Example 41. The compound was isolated asa white solid (16 mg, 62% yield). MS (apci) m/z=515.2 (M−H).

Example 46

1-(6-chloro-1-ethyl-1,2,3,4-tetrahydroquinolin-4-yl)-3-(3-methoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

The title compound was prepared utilizing6-chloro-1-ethyl-1,2,3,4-tetrahydroquinolin-4-amine dihydrochlorideinstead of 1-methyl-1,2,3,4-tetrahydroquinolin-4-amine dihydrochlorideof in the preparation outlined for Example 39, Step C. The compound wasisolated as a white solid (20 mg, 98% yield). MS (apci) m/z=440.1 (M+H).

Example 47

1-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureaStep A: Preparation of tert-butyl((1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)carbamate

To a turbid suspension of (1S,2S)-1-amino-2,3-dihydro-1H-inden-2-ol (140mg, 0.938 mmol) in DCM (4.7 mL, 0.938 mmol) was added triethylamine (262μL, 1.88 mmol), followed by Boc₂O (215 mg, 0.985 mmol) in one portion atambient temperature. The reaction was stirred for 2 days, filtered (GF/Fpaper), rinsed with DCM and concentrated. The crude product was purifiedby silica gel chromatography (3:1 hexanes/EtOAc) to yield the product aswhite solid (200 mg, 86% yield). ¹H NMR (CDCl₃) δ 7.20-7.26 (m, 4H),5.05 (br s, 1H), 4.88-4.92 (m, 1H), 4.38-4.45 (m, 1H), 4.29 (br s, 1H),3.25-3.31 (m, 1H), 2.88-2.94 (m, 1H), 1.50 (s, 9H) ppm.

Step B: Preparation of tert-butyl((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)carbamate

A mixture of tert-butyl(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-ylcarbamate (50 mg, 0.20 mmol),barium oxide (369 mg, 2.4 mmol), Ba(OH)₂ (206 mg, 1.2 mmol) and CH₃I (28mg, 0.20 mmol) in DMF (1.34 mL) was stirred at ambient temperatureovernight. The reaction mixture was poured into saturated NaHCO₃ (15mL), and the aqueous mixture was extracted with DCM (3×20 mL). Thecombined organic extracts were washed with water (3×15 mL), dried(Na₂SO₄), filtered and concentrated. The crude product was purified bysilica gel chromatography (20% EtOAc/hexanes) to yield the product aswhite waxy solid (17 mg, 32% yield). ¹H NMR (CDCl₃) δ 7.18-7.30 (m, 4H),5.08 (m, 1H), 4.72 (m, 1H), 3.93-3.98 (m, 1H), 3.50 (s, 3H), 3.24-3.30(m, 1H), 2.83-2.88 (m, 1H), 1.49 (s, 9H) ppm.

Step C: Preparation of1-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

A solution of tert-butyl(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-ylcarbamate (15.9 mg, 0.0604mmol) in hydrogen chloride (5-6 N in Isopropyl alcohol, 604 μL, 3.02mmol) was stirred at ambient temperature for 1 hour. After removal ofthe solvent under vacuum, the white solid residue was taken up in DMA(302 μL), followed by addition of phenyl2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate (19.3 mg,0.0604 mmol) and DIEA (52.6 μL, 0.302 mmol), and the reaction wasstirred at ambient temperature for 20 minutes. The reaction mixture wasdirectly purified by reverse-phase chromatography (5 to 60%acetonitrile/water) to yield the product as white solid (6 mg, 26%yield). MS (apci) m/z=389.1 (M+H).

Example 48

1-((1S,2S)-2-(2-methoxyethoxy)-2,3-dihydro-1H-inden-1-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureaStep A: Preparation of tert-butyl((1S,2S)-2-(2-methoxyethoxy)-2,3-dihydro-1H-inden-1-yl)carbamate

A mixture of tert-butyl(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-ylcarbamate (50 mg, 0.20 mmol),barium oxide (369 mg, 2.4 mmol), Ba(OH)₂ (206 mg, 1.2 mmol) and1-bromo-2-methoxyethane (28 mg, 0.20 mmol) in DMF (1.3 mL) was stirredat ambient temperature overnight. The reaction mixture was filtered(GF/F paper), rinsed with acetonitrile, concentrated and directlypurified by reverse-phase chromatography (5 to 60% acetonitrile/water)to yield the product as white solid (14 mg, 23% yield). ¹H NMR (CDCl₃) δ7.16-7.29 (m, 4H), 5.08 (m, 1H), 4.74-4.76 (m, 1H), 4.08-4.12 (m, 1H),3.87-3.92 (m, 1H), 3.73-3.79 (m, 1H), 3.55-3.59 (m, 2H), 3.38 (s, 3H),3.24-3.30 (m, 1H), 2.90-2.95 (m, 1H), 1.48 (s, 9H) ppm.

Step B: Preparation of1-((1S,2S)-2-(2-methoxyethoxy)-2,3-dihydro-1H-inden-1-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

A solution of tert-butyl(1S,2S)-2-(2-methoxyethoxy)-2,3-dihydro-1H-inden-1-ylcarbamate (14 mg,0.046 mmol) in hydrogen chloride (455 μL, 2.3 mmol) [5-6 N, IPA] wasstirred at ambient temperature for 10 minutes, then concentrated underreduced pressure. The white solid residue was taken up in DMA (228 μL),followed by addition of phenyl2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate (15 mg,0.046 mmol) and DIEA (40 μL, 0.23 mmol). The reaction was stirred atambient temperature for 1 hour, and directly purified by reverse-phasechromatography (5 to 60% acetonitrile/water) to yield the product aswhite solid (15 mg, 76% yield). MS (apci) m/z=433.2 (M+H).

Example 49

1-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((1S,2S)-2-(2-methoxyethoxy)-2,3-dihydro-1H-inden-1-yl)urea

To a turbid solution of(1S,2S)-2-(2-methoxyethoxy)-2,3-dihydro-1H-inden-1-amine hydrochloride(30 mg, 0.12 mmol) and phenyl3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate (39 mg, 0.12 mmol)in DMA (410 μL) was added DIEA (107 μL, 0.62 mmol) to obtain a clearsolution, and the reaction was stirred at ambient temperature for 30minutes. The reaction mixture was directly purified by reverse-phasechromatography (5 to 70% acetonitrile/water) to yield the product aswhite solid (27 mg, 49% yield). MS (apci) m/z=451.2 (M+H).

Example 50

1-((1R,2R)-2-(2-methoxyethoxy)-2,3-dihydro-1H-inden-1-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

The title product was prepared as described for Example 48, using(1R,2R)-1-amino-2,3-dihydro-1H-inden-2-ol instead of(1S,2S)-1-amino-2,3-dihydro-1H-inden-2-ol in the initial step. MS (apci)m/z=433.2 (M+H).

Example 51

1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((1S,2S)-2-(2-methoxyethoxy)-2,3-dihydro-1H-inden-1-yl)urea

The title product was prepared as described for Example 48, using phenyl(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)carbamate in theurea coupling step in place of phenyl2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate. MS (apci)m/z=487.2 (M+H).

Example 52

1-(4-bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((1S,2S)-2-(2-methoxyethoxy)-2,3-dihydro-1H-inden-1-yl)urea

To a solution of phenyl 3-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate (20mg, 0.0682 mmol) in DCM (136 μL) was added NBS (12.7 mg, 0.0716 mmol) inone portion, followed by pyridin-1-ium 4-methylbenzenesulfonate (PPTS,1.71 mg, 0.00682 mmol). After stirring at ambient temperature for 10minutes, (1S,2S)-2-(2-methoxyethoxy)-2,3-dihydro-1H-inden-1-aminehydrochloride (17.4 mg, 0.0716 mmol) was introduced, followed by DIEA(59.4 μL, 0.341 mmol). The reaction was stirred for 1 hour and directlypurified by reverse-phase chromatography (5 to 60% acetonitrile/water)to yield the product as white solid (17 mg, 50% yield). MS (apci)m/z=485.0 (M+H).

Example 53

1-(2,3-dihydro-1H-inden-1-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

The title product was as described for Example 49, using2,3-dihydro-1H-inden-1-amine in place of(1S,2S)-2-(2-methoxyethoxy)-2,3-dihydro-1H-inden-1-amine hydrochloride.MS (apci) m/z=376.9 (M+H).

Example 54

(S)-1-(2,3-dihydro-1H-inden-1-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

The title product was prepared as described for Example 53, using(S)-2,3-dihydro-1H-inden-1-amine instead of2,3-dihydro-1H-inden-1-amine. MS (apci) m/z=376.9 (M+H).

Example 55

1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(trans-2′-hydroxy-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-3′-yl)ureaStep A: spiro[cyclopropane-1,1′-indene]

To a suspension of N-benzyl-N,N-diethylethanaminium chloride (111 mg,0.487 mmol) in NaOH (50 wt % aqueous, 18 mL) cooled to 0° C. was addeddropwise a solution of 1H-indene (4.463 g, 38.42 mmol) and dibromoethane(6.6 mL, 76.84 mmol) in DMSO (7 mL). The reaction mixture was heated to60° C. for 5 hours then cooled to ambient temperature. The reactionmixture was diluted with H₂O (30 mL) and extracted with Et₂O (3×30 mL).The combined organic phases were washed with H₂O (30 mL), then brine(3×30 mL), then dried (MgSO₄), filtered, and concentrated. The crude oilwas purified by silica column chromatography eluting with hexanes toafford the title compound as a colorless oil (1.24 g, 23% yield). ¹H NMR(CDCl₃) δ 7.42 (m, 1H), 7.24 (m, 1H), 7.26 (m, 1H), 6.98 (m, 1H), 6.88(d, 1H), 6.23 (d, 1H), 1.70-1.65 (m, 2H), 1.63-1.59 (m, 2H).

Step B: 1a′,6a′-dihvdrospiro[cyclopropane-1,6′-indeno[1,2-b]oxirene]

To a solution of spiro[cyclopropane-1,1′-indene] (817 mg, 5.745 mmol) inMeOH (40 mL) cooled to 0° C. were added DCC (2.37 g, 11.49 mmol), KHCO₃(1.15 g, 11.49 mmol), then H₂O₂(30% aqueous, 8 mL). The reaction mixturewas allowed to warm to ambient temperature over 3 hours, then wasdiluted with saturated aqueous NaHCO₃ (50 mL) and H₂O (50 mL), andextracted with DCM (3×100 mL). The combined organic extracts were dried(MgSO₄), filtered, and concentrated to give the title compound as acolorless oil/white solid mixture, which was used in the next stepwithout further purification.

Step C: trans-3′-amino-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2′-ol

A mixture of1a′,6a′-dihydrospiro[cyclopropane-1,6′-indeno[1,2-b]oxirene] (909 mg,5.75 mmol) and concentrated NH₄OH (22 mL) were heated to 60° C. for 1hour. The reaction mixture was cooled, partially concentrated, thenpurified by reverse-phase column chromatography, eluting with 5-50%acetonitrile/water, to afford the title compound as a pale blue solid(493 mg, 49% yield). ¹H NMR (CDCl₃) δ 7.32 (m, 1H), 7.22 (m, 2H), 6.75(m, 1H), 4.18 (d, 1H), 3.98 (d, 1H), 1.99 (br s, 3H), 1.35 (m, 1H), 1.12(m, 1H), 0.97 (m, 1H), 0.69 (m, 1H).

Step D: 1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(trans-2′-hydroxy-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-3′-yl)urea

To a solution oftrans-3′-amino-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2′-ol (18.6mg, 0.106 mmol) in i-PrOH (1 mL) was added phenyl(1′,4-dimethyl-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-yl)carbamate(Intermediate 13, 41.6 mg, 0.111 mmol). The reaction mixture was heatedto 75° C. for 1 hour, cooled to ambient temperature, then purified byreverse-phase column chromatography, eluting with 5-70%acetonitrile/water with 0.1% formic acid, to afford the title compoundas a white solid (38.9 mg, 81% yield). MS (apci) m/z=455.2 (M+H).

Example 56

1-(trans-2′-hydroxy-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-3′-yl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-yl)urea

To a suspension of4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-amine(Intermediate Y4, 22.7 mg, 0.086 mmol) in DCM (1 mL) were addedtriphosgene (12.7 mg, 0.043 mmol) then DIEA (0.045 mL, 0.257 mmol). Thereaction mixture was stirred at ambient temperature for 2 hours, then asolution oftrans-3′-amino-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2′-ol(Example 55, Step C, 15 mg, 0.086 mmol) and DIEA (0.045 mL, 0.257 mmol)in DCM (1 mL) was added. The reaction mixture was stirred at ambienttemperature for 1 hour, concentrated, diluted with MeCN (1 mL) andstirred, and the resulting suspension was filtered and rinsed with Et₂O.The crude solid product was purified by silica column chromatography,eluting with 0-10% MeOH/DCM, to afford the title compound as a whitesolid (7.7 mg, 19% yield). MS (apci) m/z=467.2 (M+H).

Example 57

1-(trans-2′-hydroxy-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-3′-yl)-3-(3-(2-methoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared according to the procedure for Example 56, replacing4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-amine with3-(2-methoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-amine(Intermediate Y5, 24.1 mg, 0.086 mmol). The crude product was purifiedby preparatory TLC (1 mm plate), eluted with 10% MeOH/DCM, to afford thetitle compound as a white solid (10.4 mg, 25% yield). MS (apci)m/z=483.2 (M+H).

Example 58

1-(trans-5′,6′-difluoro-2′-hydroxy-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-3′-yl)-3-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea Step A:5,6-difluoro-2,3-dihydro-1H-inden-1-ol

To a solution of 5,6-difluoro-2,3-dihydro-1H-inden-1-one (2.0 g, 11.90mmol) in MeOH (40 mL) cooled to 0° C. was added NaBH₄ (540 mg, 14.27mmol) in portions over 5 minutes. The reaction mixture was stirred at 0°C. for 1 hour, then allowed to warm to ambient temperature and stirredfor 19 hours. The reaction mixture was diluted with H₂O (50 mL) andextracted with DCM (3×50 mL). The combined organic extracts were washedwith brine (50 mL), dried (MgSO₄), filtered, and concentrated to affordthe title compound as a colorless oil (2438 mg, 120% yield), which wasused in the next step without purification and assuming theoreticalyield. ¹H NMR (CDCl₃) δ 7.17 (dd, 1H), 7.00 (dd, 1H), 5.18 (t, 1H), 2.99(m, 1H), 2.75 (m, 1H), 2.51 (m, 1H), 1.95 (m, 1H).

Step B: 5,6-difluoro-1H-indene

To a solution of 5,6-difluoro-2,3-dihydro-1H-inden-1-ol (2024 mg, 11.90mmol) in toluene (40 mL) was added TsOH—H₂O (113 mg, 0.595 mmol). Thereaction mixture heated to 110° C. for 1 hour, then cooled to ambienttemperature. The reaction mixture was diluted with H₂O (50 mL) andextracted with DCM (3×50 mL). The combined organic extracts were dried(MgSO₄), filtered, and concentrated. The crude oil was purified bysilica column chromatography eluting with hexanes to afford a colorlessoil containing both the title compound and toluene (3.60 g, 200% yield).¹H NMR (CDCl₃) δ 7.25 (m, 2H, toluene), 7.13-7.18 (m, 6H, product 2H andtoluene 4H), 7.14 (m, 2H, product), 6.78 (m, 1H, product), 6.59 (m, 1H,product), 3.36 (m, 2H, product), 2.36 (s, 6H, toluene).

Step C:1-(trans-5′,6′-difluoro-2′-hydroxy-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-3′-yl)-3-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea

Prepared according to the procedure for Example 55, replacing 1H-indenein Step A with 5,6-difluoro-1H-indene, to afford the title compound as awhite solid (13.9 mg, 86% yield). MS (apci) m/z=491.2 (M+H).

The compounds of Table 2 were prepared according to the methods ofExamples 55 and 58, replacing Intermediate 13 with the appropriateIntermediate 3, 5, or 11.

TABLE 2 Ex. MS (apci) # Structure name m/z 59

215-(3-(trans-2′- hydroxy-2′,3′ dihydrospiro- [cyclopropane-1,1′-inden]-3′-yl)ureido)- N,4-dimethyl-1- phenyl-1H-pyrazole- 3-carboxamide432.2 (M + H) 60

1-(trans-2′-hydroxy- 2′,3′-dihydrospiro- [cyclopropane-1,1′-inden]-3′-yl)-3-(3- methoxy-4-methyl- 1-phenyl-1H-pyrazol- 5-yl)urea405.2 (M + H) 61

1-(3-ethoxy-4-methyl- 1-phenyl-1H-pyrazol- 5-yl)-3-(trans-2′-hydroxy-2′,3′-dihydro- spiro[cyclopropane- 1,1′-inden]-3′-yl)urea 419.2(M + H) 62

1-(trans-5′,6′-difluoro- 2′-hydroxy-2′,3′- dihydrospiro[cyclo-propane-1,1′-inden]- 3′-yl)-3-(3-methoxy- 4-methyl-1-phenyl-1H-pyrazol-5-yl)urea 441.2 (M + H)

Example 63

1-(1′,4-dimethyl-1-phenyl-1H1′H-[3,4′-bipyrazol]-5-yl)-3-(trans-5′-fluoro-2′-hydroxy-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-3′-yl)ureaStep A: 5-fluoro-1H-indene

Prepared according to the procedure for Example 58, Steps A-B, replacing5,6-difluoro-2,3-dihydro-1H-inden-1-one with6-fluoro-2,3-dihydro-1H-inden-1-one to afford the title compound as acolorless oil (0.78 g, 87% yield). ¹H NMR (CDCl₃) δ 7.26 (dd, 1H), 7.07(dd, 1H), 6.81-6.89 (m, 2H), 6.63 (m, 1H), 3.35 (m, 2H).

Step B: A 1:1 mixture of 5′-fluorospiro[cyclopropane-1,1′-indene] and6′-fluorospiro[cyclopropane-1,1′-indene]

Prepared according to the procedure for Example 55, Step A, replacing1H-indene with 5-fluoro-1H-indene to afford the title compound mixtureas a colorless oil (183 mg, 20% yield). ¹H NMR (CDCl₃) δ 7.30 (dd, 1H),7.09 (m, 1H), 6.92 (m, 1H), 6.81-6.86 (m, 4H), 6.66 (dd, 1H), 6.29 (d,1H), 6.19 (d, 1H), 1.65-1.70 (m, 4H), 1.54-1.58 (m, 4H).

Step C: A 1:1 mixture of 1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(trans-5′-fluoro-2′-hydroxy-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-3′-yl)ureaand 1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(trans-6′-fluoro-2′-hydroxy-2′3′-dihydrospiro[cyclopropane-1,1′-inden]-3′-yl)urea

Prepared according to the procedure for Example 55, Steps B-D, replacingspiro[cyclopropane-1,1′-indene] with a 1:1 mixture of5′-fluorospiro[cyclopropane-1,1′-indene] and6′-fluorospiro[cyclopropane-1,1′-indene] to afford the title compoundmixture as a white solid (20.3 mg, 55% yield). MS (apci) m/z=473.2(M+H).

Step D: 1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(trans-5′-fluoro-2′-hydroxy-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-3′-yl)urea

A 1:1 mixture of1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(trans-5′-fluoro-2′-hydroxy-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-3′-yl)ureaand 1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(trans-6′-fluoro-2′-hydroxy-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-3′-yl)urea(20.3 mg, 0.043 mmol) was purified by chiral HPLC on a Chiral Tech IAcolumn (4.6 mm×250 mm, 5μ), eluted with 25% EtOH/hexanes, and the secondof the two product peaks to elute was collected to afford the titlecompound as a white solid (4.5 mg, 22% yield). MS (apci) m/z=473.2(M+H). ¹H NMR (CD₂Cl₂) δ 7.80 (d, 1H), 7.45-7.53 (m, 5H), 7.38 (m, 1H),6.88 (dt, 1H), 6.74 (d, 1H), 6.67 (dd, 1H), 4.96 (d, 1H), 3.99 (d, 1H),3.91 (s, 3H), 2.14 (s, 3H), 1.31 (m, 1H), 1.00 (m, 1H), 0.85 (m, 1H),0.59 (m, 1H).

Example 64

1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(trans-6′-fluoro-2′-hydroxy-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-3′-yl)urea

Prepared according to the procedure for Example 63, but in Step D thefirst of the two product peaks to elute was collected to afford thetitle compound as a white solid (3.7 mg, 18% yield). MS (apci) m/z=473.2(M+H). ¹H NMR (CD₂Cl₂) δ 7.80 (d, 1H), 7.45-7.53 (m, 5H), 7.38 (m, 1H),6.99 (m, 1H), 6.81 (dt, 1H), 6.41 (dd, 1H), 4.92 (d, 1H), 3.97 (d, 1H),3.91 (s, 3H), 2.14 (s, 3H), 1.37 (m, 1H), 1.00 (m, 1H), 0.91 (m, 1H),0.66 (m, 1H).

Example 65

1-(1′,4-dimethyl-1-phenyl-1H,1′H-r[3,4′-bipyrazol]-5-yl)-3-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)urea

To a turbid solution of (1R,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (50mg, 0.335 mmol) in iPrOH (1.4 mL) was added phenyl(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)carbamate (125 mg,0.335 mmol) in one portion. The white suspension was stirred in a 40° C.sand bath for 2 hours, then heated to reflux. It was then slowly cooledto ambient temperature and filtered, rinsed with IPA, MeOH and ether (10mL each), yielding the title product as fine white solid (90 mg, 63%yield). ¹H NMR (400 MHz, d⁶-DMSO) δ 8.06 (s, 1H), 7.94 (br s, 1H), 7.74(s, 1H), 7.56-7.58 (m, 2H), 7.45-7.50 (m, 2H), 7.34-7.38 (m, 1H),7.12-7.17 (m, 3H), 6.91-6.93 (m, 1H), 6.78 (d, J=8.6 Hz, 1H), 5.25 (brd, J=5.5 Hz, 1H), 4.83 (br t, J=7.4 Hz, 1H), 4.13-4.18 (m, 1H), 3.88 (s,3H), 3.03-3.08 (m, 1H), 2.61-2.67 (m, 1H), 2.05 (s, 3H). MS (apci)m/z=429.2 (M+H).

Example 66

1-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-yl)urea

To an orange suspension of4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-amine(Intermediate Y4, 53.4 mg, 0.20 mmol) in DriSolve DCM (1.0 mL) was addedtriphosgene (29.8 mg, 0.10 mmol), followed by DIEA (105 μL, 0.60 mmol).After 2 hours, (1R,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (30 mg, 0.20mmol) was added in one portion. After 30 minutes, the reaction mixturewas vacuum-filtered, rinsed with DCM and ether (2 mL each), giving theproduct as white powder (54 mg, 58% yield). ¹H NMR (400 MHz, d⁶-DMSO) δ9.01 (s, 2H), 8.40 (br s, 1H), 7.62-7.64 (m, 2H), 7.49-7.54 (m, 2H),7.40-7.44 (m, 1H), 7.11-7.19 (m, 3H), 6.87-6.91 (m, 2H), 5.26 (br d,J=5.5 Hz, 1H), 4.83 (br t, J=7.8 Hz, 1H), 4.12-4.19 (m, 1H), 3.03-3.09(m, 1H), 2.66 (s, 3H), 2.61-2.66 (m, 1H), 2.15 (s, 3H). MS (apci)m/z=441.2 (M+H).

Example 67

1-(3-(2-ethoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)urea

The title product was prepared as described for Example 66, using3-(2-ethoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-amine (49.5mg, 0.17 mmol) instead of4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-amine. Theproduct was isolated as white solid (51 mg, 61% yield). ¹H NMR (400 MHz,d⁶-DMSO) δ 8.90 (s, 2H), 7.61-7.63 (m, 2H), 7.48-7.53 (m, 2H), 7.40-7.43(m, 1H), 7.25-7.31 (m, 1H), 7.14 (m, 3H), 6.84-6.91 (m, 2H), 5.26 (br d,J=5.5 Hz, 1H), 4.83 (br t, J=7.8 Hz, 1H), 4.39 (q, J=7.0 Hz, 2H),4.11-4.19 (m, 1H), 3.03-3.08 (m, 1H), 2.61-2.67 (m, 1H), 2.12 (s, 3H),1.35 (t, J=7.0 Hz, 3H). MS (apci) m/z=471.2 (M+H).

Example 68

1-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-3-(3-(2-methoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

The title product was prepared as described for Example 66, using3-(2-methoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-amine (47 mg,0.17 mmol) instead of4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-amine. Theproduct was isolated as white solid (50 mg, 62% yield). ¹H NMR (400 MHz,d⁶DMSO) δ 8.92 (s, 2H), 7.61-7.63 (m, 2H), 7.49-7.53 (m, 2H), 7.40-7.43(m, 1H), 7.24-7.30 (m, 1H), 7.11-7.17 (m, 3H), 6.85-6.92 (m, 2H), 5.26(br d, J=5.5 Hz, 1H), 4.83 (br t, J=7.4 Hz, 1H), 4.12-4.18 (m, 1H), 3.96(s, 3H), 3.03-3.09 (m, 1H), 2.61-2.67 (m, 1H), 2.12 (s, 3H). MS (apci)m/z=457.2 (M+H).

Example 69

1-(3-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)urea

The title product was prepared as described for Example 66, using5-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-1,3-dimethylpyridin-2(1H)-one(49 mg, 0.17 mmol) instead of4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-amine. Theproduct was isolated as white solid (45 mg, 54% yield). MS (apci)m/z=468.2 (M−H).

Example 70

1-((1,2-trans)-6-chloro-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-3-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea

The title product was prepared as described for Example 65, usingtrans-1-amino-6-chloro-2,3-dihydro-1H-inden-2-ol (30 mg, 0.16 mmol)instead of (1R,2R)-1-amino-2,3-dihydro-1H-inden-2-ol. The product wasisolated as crystalline white solid (65 mg, 84% yield). ¹H NMR (400 MHz,d⁶-DMSO) δ 8.03 (s, 1H), 7.99 (br s, 1H), 7.73 (s, 1H), 7.55-7.58 (m,2H), 7.45-7.49 (m, 2H), 7.33-7.37 (m, 1H), 7.15-7.22 (m, 2H), 6.93 (br,1H), 6.90 (m, 1H), 5.33 (br d, J=5.9 Hz, 1H), 4.81 (br t, J=7.8 Hz, 1H),4.14-4.21 (m, 1H), 3.87 (s, 3H), 3.00-3.06 (m, 1H), 2.57-2.63 (m, 1H),2.04 (s, 3H). MS (apci) m/z=461.1 (M−H).

Example 71

1-((1,2-trans)-6-chloro-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-yl)urea

The title product was prepared as described for Example 66, usingtrans-1-amino-6-chloro-2,3-dihydro-1H-inden-2-ol (30 mg, 0.16 mmol)instead of (1R,2R)-1-amino-2,3-dihydro-1H-inden-2-ol. The product wasisolated as crystalline white solid (12 mg, 44% yield). MS (apci)m/z=473.2 (M−H).

Example 72

1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((1,2-trans)-2-hydroxy-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl)ureaStep 1. Synthesis of 3,3-dimethyl-2,3-dihydro-1H-inden-1-ol

A light suspension of 3,3-dimethyl-2,3-dihydro-1H-inden-1-one (2.5 g, 16mmol) in DriSolve MeOH (52 mL) was first cooled in an ice-water bath,followed by addition of NaBH₄ (0.71 g, 19 mmol) in small portions. Thereaction was then warmed up to ambient temperature and stirred for 30minutes. The reaction was poured onto ice water (50 mL) in a separatoryfunnel, rinsed over with water, giving a white suspension. Thesuspension was extracted with DCM (3×50 mL). The combined organicextracts were washed with water, brine (50 mL each), dried (Na₂SO₄),filtered and concentrated to yield the crude product as clear colorlessoil (2.5 g, 99% yield), which was used for the next reaction withoutfurther purification. ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.40 (m, 1H),7.17-7.31 (m, 3H), 5.23-5.28 (m, 1H), 2.35-2.40 (m, 1H), 1.79-1.85 (m,2H), 1.39 (s, 3H), 1.22 (s, 3H).

Step 2. Synthesis of 1,1-dimethyl-1H-indene

A clear colorless solution of 3,3-dimethyl-2,3-dihydro-1H-inden-1-ol(1.83 g, 11.3 mmol) and 4-methylbenzenesulfonic acid hydrate (0.107 g,0.564 mmol) [5 mol %] in toluene (37.6 mL) was stirred at 110° C. for 2hours. The light yellowish reaction solution was cooled to ambienttemperature, diluted with Et₂O (50 mL) and washed with saturated aqueousNaHCO₃ and brine (50 mL each). The organic layer was phase-separated anddried over Na₂SO₄, then concentrated in vacuo. The crude was taken up inhexanes and purified by silica chromatography (hexanes) to yield theproduct as clear colorless oil (0.85 g, 52% yield). ¹H NMR (400 MHz,CDCl₃) δ 7.28-7.32 (m, 2H), 7.16-7.23 (m, 2H), 6.62 (d, J=6.3 Hz 1H),6.36 (d, J=5.5 Hz, 1H), 1.31 (s, 6H).

Step 3. Synthesis of 6,6-dimethyl-6,6a-dihydro-1aH-indeno[1,2-b]oxirene

To a solution of 1,1-dimethyl-1H-indene (590 mg, 4.09 mmol) in DCM (20mL) was added mCPBA (1210 mg, 4.91 mmol) in four portions at 20-minuteintervals and stirred at ambient temperature for 5 hours. The reactionwas treated with saturated aqueous NaHCO₃ (20 mL), stirred for anadditional 30 minutes, and then diluted with water and DCM (20 mL each).The aqueous layer was separated and extracted with DCM (2×30 mL). Thecombined organic layers was dried (Na₂SO₄), filtered and concentrated.The crude product was purified by silica chromatography (DCM) to yieldthe product. ¹H NMR (400 MHz, CDCl₃) δ 7.23-7.31 (m, 2H), 7.15-7.20 (m,2H), 4.24 (d, J=2.7 Hz 1H), 3.71 (d, J=2.7 Hz, 1H), 1.41 (s, 3H), 1.23(s, 3H).

Step 4. Synthesis of(2,3-trans)-3-amino-1,1-dimethyl-2,3-dihydro-1H-inden-2-ol

A mixture of 6,6-dimethyl-6,6a-dihydro-1aH-indeno[1,2-b]oxirene (0.35 g,2.2 mmol) in concentrated NH₄OH (3.8 g, 109 mmol) was stirred at 60° C.for 6 hours. The reaction mixture was briefly subjected to mild vacuum,then filtered and rinsed with water. The solid was then rinsed withsmall amount of ether to yield first batch of product as fine solid (13mg). To recover additional product, the aqueous layer and ether filtratewere concentrated and treated with reverse-phase chromatography (C18, 5to 40% acetonitrile/water) to yield a second batch of product as solid(78 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.22-7.29 (m, 3H), 7.15-7.18 (m, 1H),4.08 (d, J=8.2 Hz 1H), 3.65 (d, J=8.2 Hz, 1H), 2.79 (br, 3H), 1.36 (s,3H), 1.11 (s, 3H).

Step 5. Synthesis of 1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((1,2-trans)-2-hydroxy-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl)urea

To a clear solution of(2,3-trans)-3-amino-1,1-dimethyl-2,3-dihydro-1H-inden-2-ol (12 mg,0.0677 mmol) in iPrOH (282 μL) was added phenyl(1′,4-dimethyl-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-yl)carbamate (25.3mg, 0.0677 mmol) in one portion. The resulting milky suspension wasstirred at 40° C. for 4 hours and then brought to reflux. The reactionmixture was slowly cooled to ambient temperature and stirred for another1 hour. The reaction mixture was vacuum-filtered, rinsed with iPrOH andether (2 mL each), giving first batch product (14 mg). A second batch ofproduct was obtained from reverse-phase purification of the filtrate(C18, 5 to 60% acetonitrile/water). The two batch of product wascombined to give a white solid (26 mg, 82% yield). ¹H NMR (400 MHz,CDCl₃) δ 7.84 (s, 1H), 7.76 (s, 1H), 7.56-7.60 (m, 2H), 7.45-7.50 (m,2H), 7.35-7.39 (m, 1H), 7.25-7.29 (m, 1H), 7.16-7.20 (m, 3H), 6.94-6.96(m, 1H), 5.55 (br, 1H), 5.04 (m, 1H), 3.94 (s, 3H), 3.66 (d, J=8.2 Hz,1H), 2.29 (s, 3H), 1.34 (s, 3H), 1.10 (s, 3H). MS (apci) m/z=457.2(M+H).

Example 73

1-((1,2-trans)-2-hydroxy-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-yl)urea

To a suspension of4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-amine(Intermediate Y4, 37 mg, 0.14 mmol) in DriSolve DCM (0.7 mL) was addedtriphosgene (21 mg, 0.07 mmol), followed by DIEA (74 μL, 0.4 mmol).After 1 hour, trans-3-amino-1,1-dimethyl-2,3-dihydro-1H-inden-2-ol (25mg, 0.14105 mmol) was added in one portion. After 30 minutes, thereaction was concentrated and directly purified by reverse-phasechromatography (C18, 5 to 60% acetonitrile/water with 0.1 v/v % formicacid) to yield the product as white solid (20 mg, 29% yield). ¹H NMR(400 MHz, CDCl₃) δ 8.97 (s, 2H), 7.57-7.59 (m, 2H), 7.43-7.47 (m, 2H),7.34-7.38 (m, 1H), 7.25-7.30 (m, 2H), 7.14-7.18 (m, 2H), 6.94-6.96 (m,1H), 5.48 (br, 1H), 5.00 (br t, J=7.0 Hz, 1H), 3.72 (d, J=7.8 Hz, 1H),2.76 (s, 3H), 2.21 (s, 3H), 1.33 (s, 3H), 1.20 (m, 1H), 1.08 (s, 3H). MS(apci) m/z=467.2 (M−H).

Example 74

1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(4-methyl-3-(((R)-4-methylmorpholin-2-yl)methoxy)-1-phenyl-1H-pyrazol-5-yl)urea

To a solution of triphosgene (44.1 mg, 0.146 mmol) in dry CH₂Cl₂ (1.0mL) was added a solution of(R)-4-methyl-3-((4-methylmorpholin-2-yl)methoxy)-1-phenyl-1H-pyrazol-5-amine(Intermediate Y2, 110 mg, 0.364 mmol) and DIEA (76.0 μL, 0.437 mmol) indry CH₂Cl₂ (1.0 mL) dropwise over 45 minutes. The mixture was stirredfor 15 minutes and(1R,2R)-1-amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol(Intermediate X2, 83.5 mg, 0.437 mmol) was added. The reaction mixturewas stirred for 16 hours and was diluted with CH₂Cl₂ (4 mL). The mixturewas washed with 1M NaOH (2×) and H₂O. The organic portion was dried overNa₂SO₄, filtered, concentrated and the residue purified on a SiO₂ column(EtOAc, 5%, 10% MeOH/EtOAc). The resulting white foam was dissolved in50% CH₂C1₂-hexanes and concentrated to provide the title compound as awhite solid that was dried in vacuum (187 mg, 99%). MS (apci) m/z=520.3(M+H).

Example 75

1-((1S,2S)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(4-methyl-3-(((R)-4-methylmorpholin-2-yl)methoxy)-1-phenyl-1H-pyrazol-5-yl)urea

Using (1 S,2S)-1-amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol(Intermediate X3) in the procedure for Example 74, the title compoundwas obtained as a white solid (94 mg, 55%). MS (apci) m/z=520.3 (M+H).

Example 76

1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(4-methyl-3-(((S)-4-methylmorpholin-2-yl)methoxy)-1-phenyl-1H-pyrazol-5-yl)urea

Using(S)-4-methyl-3-((4-methylmorpholin-2-yl)methoxy)-1-phenyl-1H-pyrazol-5-amine(Intermediate Y1) in the procedure for Example 74, the title compoundwas obtained as a white solid (54 mg, 35%). MS (apci) m/z=520.3 (M+H).

Example 77

1-(trans-6,7-difluoro-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(4-methyl-3-(((R)-4-methylmorpholin-2-yl)methoxy)-1-phenyl-1H-pyrazol-5-yl)urea

Usingtrans-1-amino-6,7-difluoro-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-olin the procedure described for Example 74, the title compound wasobtained as a white solid (31 mg, 28%). MS (apci) m/z=556.3 (M+H).

Example 78

1-(trans-2′-hydroxy-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-3′-yl)-3-(4-methyl-3-(((R)-4-methylmorpholin-2-yl)methoxy)-1-phenyl-1H-pyrazol-5-yl)urea

To a solution of(R)-4-methyl-3-((4-methylmorpholin-2-yl)methoxy)-1-phenyl-1H-pyrazol-5-amine(Intermediate Y2, 51.8 mg, 0.171 mmol) in dry DMF (1.0 mL) was addedcarbonyldiimidazole (33.3 mg, 0.205 mmol) and the mixture was stirred atambient temperature for 64 hours. The reaction mixture was treated withtrans-3′-amino-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2′-ol(Example 55, Step C, 30.0 mg, 0.171 mmol) in dry DMF (0.5 mL) andstirred for 8 hours. The reaction mixture was added to H₂O (6 mL),treated with 2M NaOH to pH=1 and extracted with EtOAc (4×). The combinedextracts were washed with saturated NaCl (2×), dried overMgSO₄/activated charcoal, filtered and concentrated. The residue waspurified on a SiO₂ column (EtOAc, 5%, 10% (9:1 MeOH/NH₄OH)/EtOAc) toprovide the title compound as a white solid (36 mg, 42%). MS (apci)m/z=504.2 (M+H).

Example 79

5-(3-((1,2-trans)-6,7-difluoro-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)ureido)-N,4-dimethyl-l-phenyl-1H-pyrazole-3-carboxamideStep A: Preparation of6,7-difluoro-4,4-dimethyl-3,4-dihydronaphthalen-1(2H)-one

A stainless steel bomb equipped with a Teflon insert and a stir bar wascharged with 1,2-difluorobenzene (9.5 g, 83 mmol),5,5-dimethyldihydrofuran-2(3H)-one (9.5 g, 83 mmol), and lastly aluminumtrichloride (13 g, 100 mmol). The reaction mixture was heated to 100° C.overnight with stirring behind a safety shield. The reaction mixture wascooled to ambient temperature and the bomb was placed in an ice bathbefore opening. The reaction mixture was partitioned between water (100mL) and EtOAc (150 mL). The phases were separated and the aqueous phasewas extracted aqueous with EtOAc (2×50 mL). The combined organic phaseswere washed with saturated NaHCO₃ (100 mL), dried (MgSO₄), filtered, andconcentrated. The crude material was purified by Redi-Sep 330 silica gelcolumn, eluting with 10% EtOAc/hexanes. Yield: 4.4 g (24%).

Step B: Preparation of6,7-difluoro-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-ol

A round bottomed flask was charged with6,7-difluoro-4,4-dimethyl-3,4-dihydronaphthalen-1(2H)-one (4.4 g, 21mmol) and MeOH (75 mL). Next added NaBH₄ (0.87 g, 23 mmol) in portionsover a 15 minute period. The reaction mixture was stirred at ambienttemperature for 3 hours and then concentrated under vacuum. The residuewas partitioned between 2N NaOH (30 mL) and EtOAc (50 mL). The phaseswere separated and the aqueous phase was extracted with EtOAc (50 mL).The combined organic phases were washed with brine (30 mL), dried(MgSO₄), filtered, and concentrated. Yield: 4.6 g (93%).

Step C: Preparation of 6,7-difluoro-1,1-dimethyl-1,2-dihydronaphthalene

A round bottomed flask was charged with6,7-difluoro-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-ol (4.4 g, 21mmol), 1,2-dichloroethane (50 mL) and 4-methylbenzenesulfonic acidhydrate (0.20 g, 1.0 mmol). The reaction mixture was heated to 60° C.for 1 hour. The reaction mixture was allowed to cool to ambienttemperature. The crude reaction mixture was used directly into the nextstep without workup.

Step D: Preparation of5,6-difluoro-3,3-dimethyl-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirene

The reaction mixture from Step C was cooled in an ice bath and saturatedaqueous NaHCO₃ (50 mL) was added. 3-chlorobenzoperoxoic acid (5.6 g, 23mmol) was added in portions over a 10 min period, and the reactionmixture was allowed to warm to ambient temperature and was stirredvigorously overnight. The reaction mixture was filtered through GF/Fpaper, rinsing with DCM. The phases were separated and the aqueous phasewas extracted with DCM (50 mL). The combined organic phases were washedwith 1N NaOH (50 mL). The resulting emulsion was filtered through GF/Fpaper which allowed the phases to separate. The organic phase was driedover Na₂SO₄, filtered, and concentrated in vacuo (rotary evaporator,water temperature was set to 30° C. to avoid loss of product). The crudematerial was placed under high vacuum for 10 minutes to provide 5.7 g ofcrude product, which was used the next step without purification.

Step E: Preparation oftrans-1-amino-6,7-difluoro-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol

A stainless steel bomb equipped with a Teflon insert and a stir bar wascharged with5,6-difluoro-3,3-dimethyl-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirene (4.3g, 20 mmol), using a few mL's of EtOH to transfer, followed by additionaqueous ammonium hydroxide (30 mL). The reaction mixture was heated to90° C. in an oil bath overnight with stirring. The reaction mixture wascooled to ambient temperature and the bomb was placed in an ice bathbefore opening. The contents of the bomb were transferred to a roundbottomed flask (using EtOH to rinse the bomb) and concentrated in vacuo.EtOH (3×30 mL) was used to azeotrope residual water and ammoniumhydroxide. The residue was partitioned between 2N aqueous HCl (75 mL)and diethyl ether (75 mL). The phases were separated and the organicphase was extracted with 1N HCl (25 mL). The combined organic phaseswere extracted with diethyl ether (50 mL). The aqueous phase was chilledin an ice bath and basified with NaOH pellets (added 5-6 at a time withsome sonication to dissolve, until pH was >12). The product precipitatedout of the basic aqueous phase. The product was extracted with 2:1diethyl ether/EtOAc (3×50 mL). The combined organic phases were dried(Na₂SO₄), filtered, and concentrated to give the desired product. Yield:1.7 g (33%).

Step F: Preparation of5-(3-((1,2-trans)-6,7-difluoro-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)ureido)-N,4-dimethyl-1-phenyl-1H-pyrazole-3-carboxamide

A vial was charged with5-amino-N,4-dimethyl-1-phenyl-1H-pyrazole-3-carboxamide (Intermediate10; 25 mg, 0.11 mmol), DCM (0.5 mL) andN-ethyl-N-isopropylpropan-2-amine (58 μL, 0.33 mmol). Triphosgene (20mg, 0.066 mmol) was added, and the reaction mixture was stirred for 15minutes.trans-1-amino-6,7-difluoro-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol(25 mg, 0.11 mmol) was added, followed byN-ethyl-N-isopropylpropan-2-amine (58 μL, 0.33 mmol). The reactionmixture was stirred over the weekend for convenience. The reactionmixture was diluted with water and DCM. The phases were separated andthe aqueous phase was extracted with DCM. The combined organic phaseswere dried (MgSO₄), filtered, and concentrated. The crude material waspurified by preparative HPLC using reverse phase YMC ODS-AQ (250×20 mm)column. Fractions containing the product were pooled and concentrated,and then partitioned between EtOAc (10 mL) and saturated NaHCO₃ (10 mL).The aqueous phase was extracted with EtOAc (2×10 mL). The combinedorganic phases were dried (MgSO₄), filtered, and concentrated. Theproduct was further purified by preparative TLC (0.5 mm thickness,Rf=0.60) eluting with 10% MeOH/DCM. Yield: 9 mg (17%). MS m/z (APCI-neg)M−1=482.2.

Example 80

1-((1,2-trans)-6,7-difluoro-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea

The title compound was prepared from(1,2-trans)-1-amino-6,7-difluoro-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol(Example 79, Step E; 25 mg, 0.11 mmol) and1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-amine (Intermediate 12,Step C; 28 mg, 0.11 mmol) according to the procedure described forExample 79, Step F. Yield: 9 mg (16%). MS m/z (APCI-pos) M+1=507.2.

Example 81

1-((1,2-trans)-6,7-difluoro-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(4-methyl-3-((1-methylpiperidin-4-yl)methoxy)-1-phenyl-1H-pyrazol-5-yl)urea

The title compound was prepared from(1,2-trans)-1-amino-6,7-difluoro-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol(Example 79, Step E; 25 mg, 0.11 mmol) and4-methyl-3-((1-methylpiperidin-4-yl)methoxy)-1-phenyl-1H-pyrazol-5-amine(Intermediate Y3; 33 mg, 0.11 mmol) according to the procedure describedfor Example 79, Step F. Yield: 10 mg (16%). MS m/z (APCI-pos) M+1=554.3.

Example 82

1-((1,2-trans)-6,7-difluoro-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3-methoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

The title compound was prepared fromtrans-1-amino-6,7-difluoro-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol(Example 79, Step E; 25 mg, 0.11 mmol) and3-methoxy-4-methyl-1-phenyl-1H-pyrazol-5-amine (Intermediate 2; 22 mg,0.11 mmol) according to the procedure described for Example 79, Step F.Yield: 6 mg (12%). MS m/z (APCI-neg) M−1=455.1.

Example 83

1-((1,2-trans)-6,7-difluoro-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(4-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)urea

The title compound was prepared fromtrans-1-amino-6,7-difluoro-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol(Example 79, Step E; 25 mg, 0.11 mmol) and5-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-1-methylpyridin-2(1H)-one(Intermediate 7; 31 mg, 0.11 mmol) according to the procedure describedfor Example 79, Step F. Yield: 2 mg (3%). MS m/z (APCI-neg) M−1=532.2.

Example 84

1-((1,2-trans)-6,7-difluoro-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-yl)urea

The title compound was prepared fromtrans-1-amino-6,7-difluoro-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol(Example 79, Step E; 25 mg, 0.11 mmol) and4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-amine(Intermediate Y4, 29 mg, 0.11 mmol) according to the procedure describedfor Example 79, Step F. Yield: 8 mg (14%). MS m/z (APCI-neg) M−1=517.2.

Example 85

5-(3-((r-1t-2,t-3)-2-hydroxy-3-methoxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)ureido)-N,4-dimethyl-l-phenyl-1H-pyrazole-3-carboxamideStep A: Preparation of 1-methylnaphthalen-2-ol

A round bottomed flask was charged with naphthalen-2-ol (100 g, 694mmol) and anhydrous MeOH (250 mL). The solution was chilled in an icebath and sodium methanolate (158 mL, 694 mmol; 25 wt % in MeOH) wasadded by addition funnel over 1 hour under a stream of N₂ with stirring.The ice bath was removed and the reaction mixture was stirred for 30minutes at ambient temperature. The reaction mixture was concentratedmixture in vacuo, using toluene (3×150 mL) to azeotrope residual MeOH.The resulting solids were dried under high vacuum. The solids weresuspended in anhydrous toluene (500 mL), and iodomethane (129 mL, 2076mmol) was added while stirring. The mixture was heated to reflux (oilbath temp=70° C.) under N₂ overnight. Due to incomplete reaction,additional iodomethane (100 mL) was added, and the reaction mixture washeated at 70-75° C. for 2 days. The reaction mixture was cooled toambient temperature and concentrated in vacuo. The residue waspartitioned between 1N NaOH (600 mL) and diethyl ether (400 mL). Thephases were separated and the organic phase was extracted with 1N NaOH(200 mL). The combined aqueous phases were extracted with diethyl ether(300 mL). The aqueous phases was then chilled in an ice bath, andcarefully acidified with concentrated HCl (approximately 70 mL), andthen extracted with diethyl ether (3×100 mL). The combined organicphases were dried (MgSO₄), filtered, and concentrated, then dried underhigh vacuum for one hour to provide 57.8 g of brown solids containing a69:31 ratio of desired 1-methylnaphthalen-2-ol to starting materialnaphthalen-2-ol was obtained. The mixture was carried forward to thenext step without separation.

Step B: Preparation of 1,1-dimethylnaphthalen-2(1H)-one

A round bottomed flask was charged with 1-methylnaphthalen-2-ol fromStep A (57.8 g, 365 mmol) and anhydrous MeOH (100 mL). The solution waschilled in an ice bath and sodium methanolate (83.1 mL, 365 mmol; 25 wt% in MeOH) was added dropwise under N₂ by addition funnel whilestirring. The ice bath was removed and the reaction mixture was stirredfor 30 minutes at ambient temperature, then concentrated in vacuo.Toluene (3×100 mL) was used to azeotrope residual MeOH. To the resultingsolids was added iodomethane (203 mL, 3257 mmol), and the mixture washeated to reflux (oil bath temp=50° C.) for 4 hours with stirring. Dueto incomplete reaction, added toluene (300 mL) and DMF (50 mL) andincreased the heat to 60° C. 1H NMR analysis of the crude indicated thestarting material had been consumed. The reaction was allowed to cool toambient temperature, then concentrated in vacuo. The residue waspartitioned between 1N NaOH (300 mL) and diethyl ether (300 mL). Thephases were separated and the aqueous phase was extracted with diethylether (2×100 mL). The combined organic phases were washed with water(200 mL), brine (200 mL), dried (MgSO₄), filtered, and concentrated to adark oil (75 g). The crude material was purified by Biotage Flash 75 Lsilica gel column, eluting with hexanes followed by 10% EtOAc/hexanes.Yield of 1,1-dimethylnaphthalen-2(1H)-one: 6.5 g (9%). The majorby-product (which eluted from silica gel column with hexanes) was2-methoxy-1-methylnaphthalene resulting from O-methylation.

Step C: Preparation of 1,1-dimethyl-1,2-dihydronaphthalen-2-ol

A round bottomed flask was charged with 1,1-dimethylnaphthalen-2(1H)-one(3.4 g, 20 mmol) and MeOH (50 mL). The solution was chilled in an icebath and NaBH₄ (0.76 g, 20 mmol) was added in portions over 10 minutes.The reaction mixture was stirred for 10 minutes after addition wascompletion. The ice bath was removed and the reaction mixture wasstirred for 30 minutes at ambient temperature. The reaction mixture waschilled in ice bath and carefully quenched with 2N NaOH (20 mL), andthen partially concentrated mixture in vacuo. The residue was extractedwith EtOAc (3×25 mL). The combined organic phases were washed with brine(30 mL), dried (MgSO₄), filtered, and concentrated. Yield: 3.2 g (87%).

Step D: Preparation of 2-methoxy-1,1-dimethyl-1,2-dihydronaphthalene

A round bottomed flask was charged with1,1-dimethyl-1,2-dihydronaphthalen-2-ol (1.74 g, 10 mmol) and anhydrousDMF (30 mL). The solution was chilled in an ice bath and sodium hydride(0.480 g, 12.0 mmol; 60% in oil) was added in portions over 10 minutesunder a stream of N₂. The reaction mixture was stirred for 30 minutes inice bath, then added iodomethane (0.93 mL, 15 mmol). The ice bath wasremoved and the reaction mixture was warmed to ambient temperature andstirred for 30 minutes. The reaction mixture was carefully quenched withsaturated aqueous NH₄Cl (20 mL), and the aqueous layer was extractedwith EtOAc (2×30 mL). The combined organic phases were washed with water(2×20 mL), brine (20 mL), dried (MgSO₄), filtered, and concentrated toprovide the desired product. Yield: 1.98 g (95%).

Step E: Preparation of(r-1a,c-2,c-7b)-2-methoxy-3,3-dimethyl-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirene

2-methoxy-1,1-dimethyl-1,2-dihydronaphthalene (1.5 g, 8.0 mmol) and1,2-dichloroethane (50 mL) were combined in a flask, and the flask wasplaced in an ice bath. Saturated aqueous NaHCO₃ (50 mL) was added,followed by addition of 3-chlorobenzoperoxoic acid (3.9 g, 16 mmol). Thereaction mixture was allowed to warm to ambient temperature and wasstirred overnight. The mixture was diluted with water (30 mL) and DCM(30 mL). The phases were separated and the aqueous phase was extractedwith DCM (30 mL). The combined organic phases were washed with 2N NaOH(30 mL), dried (MgSO₄), filtered, and concentrated to provide thedesired product. Yield: 1.8 g. Relative stereochemical assignments werebased on NOE correlations between the gem-dimethyl hydrogen atoms andthe saturated ring hydrogen atoms. The crude product carried into nextstep without purification.

Step F: Preparation of(r-1,t-2,t-3)-1-amino-3-methoxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol

Title compound prepared from(r-1a,c-2,c-7b)-2-methoxy-3,3-dimethyl-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirene(1.6 g, 7.83 mmol) according to the procedure described for Example 79,Step E. Yield: 538 mg (28%).

Step G: Preparation of5-(3-((r-1,t-2,t-3)-2-hydroxy-3-methoxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)ureido)-N,4-dimethyl-1-phenyl-1H-pyrazole-3-carboxamide

Title compound prepared from(r-1,t-2,t-3)-1-amino-3-methoxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-olfrom Step F (20 mg, 0.090 mmol) and5-amino-N,4-dimethyl-1-phenyl-1H-pyrazole-3-carboxamide (Intermediate10; 21 mg, 0.090 mmol) according to the procedure described for Example79, Step F. Yield: 12 mg (27%). MS m/z (APCI-neg) M−1=476.2.

Example 86

1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((r-1,t-2,t-3)-2-hydroxy-3-methoxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-yl)urea

The title compound was prepared from(r-1,t-2,t-3)-1-amino-3-methoxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol(Example 85, Step F; 20 mg, 0.090 mmol) and1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-amine (Intermediate 12,Step C; 23 mg, 0.090 mmol) according to the procedure described forExample 79, Step F. Yield: 10 mg (22%). MS m/z (APCI-pos) M+1=501.2.

Example 87

1-((r-1, t-2,t-3)-2-hydroxy-3-methoxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(4-methyl-3-((1-methylpiperidin-4-yl)methoxy)-1-phenyl-1H-pyrazol-5-yl)urea

The title compound was prepared from(r-1,t-2,t-3)-1-amino-3-methoxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol(Example 85, Step F; 20 mg, 0.090 mmol) and4-methyl-3-((1-methylpiperidin-4-yl)methoxy)-1-phenyl-1H-pyrazol-5-amine(Intermediate Y3; 27 mg, 0.090 mmol) according to the proceduredescribed for Example 79, Step F. Yield: 12 mg (24%). MS m/z (APCI-pos)M+1=548.3.

Example 88

5-(3-((1,2-trans)-6-fluoro-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)ureido)-N,4-dimethyl-1-phenyl-1H-pyrazole-3-carboxamideStep A: Preparation of6-fluoro-4,4-dimethyl-3,4-dihydronaphthalen-1(2H)-one

5,5-Dimethyldihydrofuran-2(3H)-one (10.0 g, 87.6 mmol) and fluorobenzene(16.8 g, 175 mmol) were combined in a sealed tube and AlCl₃ (26.9 g, 202mmol) added in small portions over 2 hours. The sealed tube was heatedto 100° C. overnight with stirring. After cooling to ambienttemperature, the reaction mixture was poured onto ice (75 mL) using moreice (50 mL) and EtOAc (100 mL) to help transfer. The phases wereseparated and the aqueous phase was extracted with EtOAc (2×25 mL). Thecombined organic phases were washed with saturated aqueous NaHCO₃ (50mL). The resulting emulsion was filtered through GF/F paper, rinsingwith EtOAc. The phases were separated and the organic phase was dried(MgSO₄) filtered, and concentrated. The crude material was purified byRedi-Sep 330 silica gel column, eluting with a gradient of 5%-10%EtOAc/hexanes. ¹H NMR indicated a 70:30 ratio of two regioisomers:6-fluoro-4,4-dimethyl-3,4-dihydronaphthalen-1(2H)-one and7-fluoro-4,4-dimethyl-3,4-dihydronaphthalen-1(2H)-one, respectively.Yield of mixture: 2.7 g (11%). The mixture was used directly in the nextstep.

Step B: Preparation of6-fluoro-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-ol

A round bottomed flask was charged with a 70:30 mixture of the tworegioisomers from step A(6-fluoro-4,4-dimethyl-3,4-dihydronaphthalen-1(2H)-one and7-fluoro-4,4-dimethyl-3,4-dihydronaphthalen-1(2H)-one, respectively)(2.7 g, 14.0 mmol) and MeOH (30 mL). The solution was chilled in an icebath. NaBH₄ (0.585 g, 15.5 mmol) was added in portions over a 15 minutesperiod, and the reaction mixture was stirred at ambient temperature for2 hours. A majority of the solvent was removed in vacuo. The residue waspartitioned between 2N NaOH (20 mL) and EtOAc (30 mL). The phases wereseparated and the aqueous phase was extracted with EtOAc (20 mL). Thecombined organic phases were washed with brine (20 mL), dried (MgSO₄),filtered, and concentrated. The two regioisomers were separated byRediSep 330 silica gel column eluting with a gradient of 20%-30%EtOAc/hexanes. Yield of6-fluoro-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-ol: 1.48 g (49%).Yield of 7-fluoro-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-ol: 601 mg(13%).

Step C: Preparation of 7-fluoro-1,1-dimethyl-1,2-dihydronaphthalene

A round bottomed flask was charged with6-fluoro-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-ol (1.48 g, 7.62mmol), 1,2-dichloroethane (20 mL) and 4-methylbenzenesulfonic acidhydrate (0.0725 g, 0.381 mmol). The reaction mixture was heated to 60°C. for 1 hour. The reaction mixture was cooled to ambient temperature,and then used directly into next step without workup or purification.

Step D: Preparation of5-fluoro-3,3-dimethyl-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirene

The reaction mixture containing7-fluoro-1,1-dimethyl-1,2-dihydronaphthalene from Step C (1.34 g, 7.60mmol) was stirred in an ice bath and saturated aqueous NaHCO₃ (20 mL)was added. 3-Chlorobenzoperoxoic acid (2.81 g, 11.4 mmol) was added andthe reaction mixture was allowed to warm to ambient temperature, andstirring was continued overnight. The reaction mixture diluted withwater (20 mL) and DCM (20 mL). The phases were separated and the aqueousphase was extracted with DCM (20 mL). The combined organic phases werewashed with 2N NaOH (20 mL), dried (MgSO₄), filtered, and concentrated.The crude was used in the next step without purification. Yield: 1.49 g(71%).

Step E: Preparation oftrans-1-amino-6-fluoro-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol

A stainless steel bomb equipped with a Teflon insert and a stir bar wascharged with5-fluoro-3,3-dimethyl-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirene (1.46 g,7.60 mmol) using a few mL's of EtOH to transfer, and aqueous ammoniumhydroxide (15 mL). The reaction mixture was heated to 90° C. in an oilbath overnight. The reaction mixture was cooled to ambient temperatureand the bomb was placed in an ice bath before opening. The contents ofthe bomb were transferred to a round bottomed flask using EtOH, and thenconcentrated in vacuo. The crude mixture was partitioned between 1Naqueous HCl (15 mL) and diethyl ether (15 mL). The phases were separatedand the organic phase was extracted with 1N HCl (5 mL). The combinedaqueous phases were extracted with diethyl ether (20 mL). The aqueousphases were chilled in an ice bath and basified with NaOH pellets (addeda few at a time with sonication to dissolve, until pH was >12). Theproduct precipitated out of basic aqueous phase. The product wasextracted with 20% EtOAc in diethyl ether (2×20 mL). The combinedorganic phases were dried (MgSO₄), filtered, and concentrated in vacuoto provide the crude desired product. Yield: 572 mg (32%). The crudecarried was used directly in the next step without purification.

Step F: Preparation of5-(3-((1,2-trans)-6-fluoro-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)ureido)-N,4-dimethyl-1-phenyl-1H-pyrazole-3-carboxamide

The title compound was prepared fromtrans-1-amino-6-fluoro-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol(20 mg, 0.096 mmol) and5-amino-N,4-dimethyl-1-phenyl-1H-pyrazole-3-carboxamide (Intermediate10, 22 mg, 0.096 mmol) according to the procedure for Example 79, StepF. Yield: 12 mg (26%). MS m/z (APCI-neg) M−1=464.2.

Example 89

1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((1,2-trans)-6-fluoro-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)urea

The title compound was prepared fromtrans-1-amino-6-fluoro-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol(Example 88, Step E; 20 mg, 0.096 mmol) and1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-amine (Intermediate 12,24 mg, 0.096 mmol) according to the procedure for Example 79, Step F.Yield: 9 mg (19%). MS m/z (APCI-pos) M+1=489.2.

Example 90

1-((1,2-trans)-6-fluoro-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(4-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)urea

The title compound was prepared fromtrans-1-amino-6-fluoro-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol(Example 88, Step E; 20 mg, 0.096 mmol) and5-(5-amino-4-methyl-1-phenyl-H-pyrazol-3-yl)-1-methylpyridin-2(1H)-one(Intermediate 7, 27 mg, 0.096 mmol) according to the procedure forExample 79, Step F. Yield: 11 mg (22%). MS m/z (APCI-neg) M−1=514.2.

Example 91

5-(3-((1,2-trans)-7-fluoro-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)ureido)-N,4-dimethyl-1-phenyl-1H-pyrazole-3-carboxamideStep A: Preparation of 6-fluoro-1,1-dimethyl-1,2-dihydronaphthalene

Prepared from 7-fluoro-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-ol(Example 88, Step B; 601 mg, 3.09 mmol) according to the procedure forExample 88, Step C. Crude reaction mixture was carried forward into nextstep without workup or purification.

Step B: Preparation of6-fluoro-3,3-dimethyl-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirene

Prepared from the crude reaction mixture containing6-fluoro-1,1-dimethyl-1,2-dihydronaphthalene from Step A according tothe procedure for Example 88, Step D. Purified crude by Red-Sep 120silica gel column eluting with a gradient of 5%-10% EtOAc/hexanes.Yield: 110 mg (17%). Structural assignment was based on ¹H NMR NOEcorrelations.

Step C: Preparation oftrans-1-amino-7-fluoro-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol

Prepared from6-fluoro-3,3-dimethyl-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirene (110 mg,0.572 mmol) according to the procedure for Example 88, Step E. Yield: 93mg (70%).

Step D: Preparation of5-(3-((1,2-trans)-7-fluoro-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)ureido)-N,4-dimethyl-1-phenyl-1H-pyrazole-3-carboxamide

Prepared fromtrans-1-amino-7-fluoro-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol(20 mg, 0.096 mmol) and5-amino-N,4-dimethyl-1-phenyl-1H-pyrazole-3-carboxamide (Intermediate10, 22 mg, 0.096 mmol) according to the procedure for Example 7, Step F.Yield: 9 mg (20%). MS m/z (APCI-neg) M−1=464.2.

Example 92

1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((1,2-trans)-7-fluoro-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)urea

The title compound was prepared fromtrans-1-amino-7-fluoro-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol(Example 91, Step C; 20 mg, 0.096 mmol) and1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-amine (Intermediate 12,24 mg, 0.096 mmol) according to the procedure for Example 79, Step F.Yield: 12 mg (24%). MS m/z (APCI-pos) M+1=489.2.

Example 93

1-((1,2-trans)-7-fluoro-2-hydroxy-4,4-dimethyl-12,3,4-tetrahydronaphthalen-1-yl)-3-(4-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)urea

The title compound was prepared fromtrans-1-amino-7-fluoro-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol(Example 91, Step C; 20 mg, 0.096 mmol) and5-(5-amino-4-methyl-1-phenyl-H-pyrazol-3-yl)-1-methylpyridin-2(1H)-one(Intermediate 7, 27 mg, 0.096 mmol) according to the procedure forExample 79, Step F. Yield: 10 mg (19%). MS m/z (APCI-neg) M−1=514.2.

Example 94

1-(trans-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3-(2-hydroxyethyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)ureaStep A: Preparation of1-(3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-(trans-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)urea

A mixture of phenyl(3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)carbamate(13.4 mg, 0.03 mmol),trans-1-amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol(Intermediate X1, 12.5 mg, 0.033 mmol) and triethylamine (15.0 mg, 0.15mmol) were combined in 0.2 mL of DMF and stirred at ambient temperaturefor 1 hour. The mixture was loaded onto a samplet and purified byreverse-phase column chromatography, eluting with 0-70%acetonitrile/water, to afford the title compound (7.5 mg, 0.014 mmol,46% yield). MS (apci) m/z=549.3 (M+H).

Step B: Preparation of1-(trans-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3-(2-hydroxyethyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

1-(3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-(trans-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)urea(7.0 mg, 0.0128 mmol) and HCl (21.3 μL, 0.128 mmol) (in IPA) werecombined in 1 mL of DCM and stirred at ambient temperature for 1 hour.The mixture was concentrated and purified by reverse-phase columnchromatography, eluting with 0-60% acetonitrile/water, to afford thetitle compound (2.3 mg, 0.00529 mmol, 41.5% yield). MS (apci) m/z=435.2(M+H).

Example 95

1-(trans-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(4-methyl-5-oxo-2-phenyl-2,5-dihydro-1H-pyrazol-3-yl)urea

CDI (565.6 mg, 3.488 mmol),5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one (Intermediate 2, Step A,300 mg, 1.586 mmol) and NEt₃ (497.2 μL, 3.567 mmol) were combined in 3mL of DMF and stirred at ambient temperature overnight. Additional CDI(200 mg) was added and the reaction stirred for 3 days. 1 mL of theresultant solution was added to a solution oftrans-1-amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol(Intermediate X1, 50 mg, 0.26 mmol) and NEt₃ (109 μL, 0.78 mmol) in 0.2mL of DMF. The mixture was and stirred at ambient temperature for 1hour, loaded onto a samplet and purified by reverse-phase columnchromatography, eluting with 0-70% acetonitrile/water, to afford thetitle compound (36 mg, 0.089 mmol, 34% yield). MS (apci) m/z=407.2(M+H).

Example 96

1-(6-(methoxymethyl)-1-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-4-yl)-3-(4-methyl-5-oxo-2-phenyl-2,5-dihydro-1H-pyrazol-3-yl)urea

CDI (565.6 mg, 3.488 mmol),5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one (Intermediate 2, Step A,300 mg, 1.586 mmol) and NEt₃ (497 μL, 3.567 mmol) were combined in 3 mLof DMF and stirred at ambient temperature overnight. Additional CDI (200mg) was added and the reaction stirred for 3 days. 0.1 mL of theresultant solution were added to a solution of6-(methoxymethyl)-1-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-4-amine(10 mg, 0.035 mmol), and NEt₃ (11 μL, 0.078 mmol) in 0.1 mL of DMF. Themixture was and stirred at ambient temperature for 1 hour, loaded onto asamplet and purified by reverse-phase column chromatography, elutingwith 0-50% acetonitrile/water, to afford the title compound (6.9 mg,0.014 mmol, 40% yield). MS (apci) m/z=504.2 (M+H).

Example 97

1-(trans-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3-methoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

1-(trans-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(4-methyl-5-oxo-2-phenyl-2,5-dihydro-1H-pyrazol-3-yl)urea(Example 95, 77 mg, 0.19 mmol) was dissolved in DCM (10 mL) and MeOH (10mL) and a solution of TMS-Diazomethane in hexanes (142 μL, 0.28 mmol)was added dropwise. The reaction was stirred at ambient temperature for1 hour, concentrated and purified by reverse-phase columnchromatography, eluting with 0-70% acetonitrile/water, to afford thetitle product as white solid (40 mg, 0.095 mmol, 50% yield) (peak 2, MS(apci) m/z=421.1 (M+H)) and regioisomeric side-product1-(1,4-dimethyl-5-oxo-2-phenyl-2,5-dihydro-1H-pyrazol-3-yl)-3-(trans-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)urea(11 mg, 0.026 mmol, 14% yield) (peak 1, MS (apci) m/z=421.2 (M+H)).

Example 98

trans-8-(3-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)ureido)-7-hydroxy-5,5-dimethyl-5,6,7,8-tetrahydronaphthalene-2-carboxamideStep A: Preparation of methyl3,3-dimethyl-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirene-6-carboxylate

6-bromo-1,1-dimethyl-1,2-dihydronaphthalene (200 mg, 0.843 mmol)(prepared as described in Step B, Intermediate X4) was dissolved in THF(10 mL) and cooled to −78° C. A 1.7N solution of tert-BuLi in pentane(1.141 mL, 1.94 mmol) was added dropwise and the reaction was stirred at−78° C. for 20 minutes. Methyl chloroformate (130 μL, 1.69 mmol) wasadded and the reaction was allowed to warm to ambient temperatureovernight, quenched with brine (10 mL) and extracted with EtOAc (2×25mL). The combined organic extracts were filtered through phase separatorpaper and concentrated. The crude product was purified by silica gelcolumn, eluting with 0-10% EtOAc/hexanes, to afford methyl5,5-dimethyl-5,6-dihydronaphthalene-2-carboxylate (69 mg, 0.319 mmol,37.8% yield) which was dissolved in DCM (5 mL) and NaHCO₃ (saturatedaqueous, 5 ml) and stirred at 0° C. 3-chlorobenzoperoxoic acid (87 mg,0.35 mmol) was added and the reaction was allowed to warm to ambienttemperature overnight. The mixture was extracted with several portionsof DCM, and the combined organic extracts were filtered through phaseseparator paper and concentrated to afford methyl3,3-dimethyl-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirene-6-carboxylate (66mg, 0.28 mmol, 89% yield). 1H NMR (CDCl₃) 8.10-8.12 (m, 1H), 7.96-8.00(m, 1H), 7.41-7.46 (m, 1H), 3.90-3.95 (m, 4H), 3.72-3.77 (m, 1H),2.18-2.28 (s, 6H), 1.18-1.90 (m, 1H), 1.37 (s, 1H), 1.32 (s, 1H) ppm.

Step B: Preparation of “Solution A”

CDI (144 mg, 0.534 mmol), 3,4-dimethyl-1-phenyl-1H-pyrazol-5-amine (100mg, 0.534 mmol) and NEt₃ (250 μL, 1.79 mmol) were combined in 1.75 mL ofDMF and stirred at ambient temperature over the weekend. The resultantsolution was used in the procedure described below.

Step C: Preparation oftrans-8-(3-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)ureido)-7-hydroxy-5,5-dimethyl-5,6,7,8-tetrahydronaphthalene-2-carboxamide

methyl3,3-dimethyl-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirene-6-carboxylate (66mg, 0.2841 mmol) and concentrated ammonium hydroxide (3.161 mL, 28.41mmol) were combined in a sealed vessel and stirred in a 50° C. sand bathfor 5 hour. The reaction was cooled, concentrated and dissolved in DMF(1 mL). 1052 μL of “Solution A” were added followed by NEt₃ (196 μL,1.40 mmol). The reaction was stirred at ambient temperature for 1 hour,loaded onto a samplet and purified by reverse-phase columnchromatography, eluting with 0-70% acetonitrile/water, to afford thetitle product as white solid (4.1 mg, 0.00916 mmol, 3.26% yield) (peak2, MS (apci) m/z=448.3 (M+H)), as well as a side-producttrans-8-(3-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)ureido)-7-hydroxy-5,5-dimethyl-5,6,7,8-tetrahydronaphthalene-2-carboxylicacid (11.3 mg, 0.0252 mmol, 8.97% yield) (peak 1, (MS (apci) m/z=449.2(M+H)).

Example 99

trans-methyl8-(3-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)ureido)-7-hydroxy-5,5-dimethyl-5,6,7,8-tetrahydronaphthalene-2-carboxylate

trans-8-(3-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)ureido)-7-hydroxy-5,5-dimethyl-5,6,7,8-tetrahydronaphthalene-2-carboxylicacid (Example 98 Side Product, 5.0 mg, 0.011 mmol) was dissolved in MeOH(0.5 mL) and DCM (0.5 mL) and a 2M solution of TMS-Diazomethane inhexanes (11.1 μL, 0.022 mmol) was added. The reaction was stirred for 1hour, formic acid (1 drop) was added and the reaction was concentratedto afford trans-methyl8-(3-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)ureido)-7-hydroxy-5,5-dimethyl-5,6,7,8-tetrahydronaphthalene-2-carboxylate(5.10 mg, 0.011 mmol, 98.9% yield). MS (apci) m/z=463.3 (M+H).

Example 100

(1-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)-3-(trans-2-hydroxy-7-(hydroxymethyl)-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)urea

trans-methyl8-(3-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)ureido)-7-hydroxy-5,5-dimethyl-5,6,7,8-tetrahydronaphthalene-2-carboxylate(10 mg, 0.0216 mmol) was dissolved in THF (1 mL) and cooled to 0° C. A1M solution of LiAlH₄ in THF (21.6 μl, 0.0216 mmol) was added and thereaction was allowed to warm to ambient temperature overnight. Sodiumsulfate decahydrate (69 mg, 0.22 mmol) was added and the reaction wasstirred for 2 hours, filtered and concentrated. The crude product waspurified by reverse-phase column chromatography, eluting with 0-60%acetonitrile/water, to afford1-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)-3-(trans-2-hydroxy-7-(hydroxymethyl)-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)urea(4.2 mg, 0.01 mmol, 44.7% yield). MS (apci) m/z=435.2 (M+H).

The compounds listed in Table 3 were prepared in a similar fashion asdescribed in Example 1, replacing 1,2,3,4-tetrahydronaphthalen-1-amineand phenyl 1′,4-dimethyl-1-phenyl-1H, 1′H-3,4′-bipyrazol-5-ylcarbamatewith the appropriate amine and phenylcarbamate starting materials,respectively.

TABLE 3 Example MS (apci) # Structure Name m/z 101

1-(1′,4-dimethyl- 1-phenyl-1H,1′H- [3,4′-bipyrazol]- 5-yl)-3-(trans-2-hydroxy-1,2,3,4- tetrahydro- naphthalen-1- yl)urea 443.2 (M + H) 102

1-(1′,4-dimethyl- 1-phenyl-1H,1′H- [3,4′-bipyrazol]- 5-yl)-3-(trans-2-hydroxy-7- (methoxymethyl)- 4,4-dimethyl- 1,2,3,4-tetrahydro-naphthalen-1-yl)- urea 515.3 103

(S)-1-(1′,4-di- methyl-1-phenyl- 1H,1′H-[3,4′- bipyrazol]-5-yl)-3-(6-fluoro- 1,2,3,4-tetra- hydronaphthalen- 1-yl)urea 445.2 (M + H) 104

1-(trans-7-chloro- 2-hydroxy-4,4- dimethyl-1,2,3,4- tetrahydro-naphthalen-1-yl)- 3-(1′,4-dimethyl- 1-phenyl-1H,1′H- [3,4′-bipyrazol]-5-yl)urea 505.3 (M + H) 105

1-(1′,4-dimethyl- 1-phenyl-1H,1′H- [3,4′-bipyrazol]- 5-yl)-3-(trans-2-hydroxy-4,4- dimethyl-1,2,3,4- tetrahydro- naphthalen-1- yl)urea 471.2(M + H) 106

1-(trans-2-hydroxy- 4,4-dimethyl- 1,2,3,4-tetrahydro- naphthalen-1-yl)-3-(4-methyl-3-(1- methyl-6-oxo-1,6- dihydropyridin-3- yl)-1-phenyl-1H-pyrazol-5-yl)urea 496.2 (M − H) 107

1-(trans-2-hydroxy- 4,4-dimethyl- 1,2,3,4-tetrahydro- naphthalen-1-yl)-3-(4-methyl-3-(1- methyl-2-oxo-1,2- dihydropyridin-4- yl)-1-phenyl-1H-pyrazol-5-yl)urea 496.2 (M − H) 108

1-(trans-2-hydroxy- 4,4-dimethyl- 1,2,3,4-tetrahydro- naphthalen-1-yl)-3-(2-phenyl-4,6- dihydro-2H-furo- [3,4-c]pyrazol-3- yl)urea 517.2 (M −H) 109

1-(1′,4-dimethyl- 1-phenyl-1H,1′H- [3,4′-bipyrazol]- 5-yl)-3-(6-(methoxymethyl)- 1-methyl-2-(2,2,2- trifluoroethyl)- 1,2,3,4-tetrahydro-isoquinolin-4- yl)urea 568.3 (M + H) 110

5-(3-(6-(methoxy- methyl)-1-methyl- 2-(2,2,2-trifluoro- ethyl)-1,2,3,4-tetrahydroiso- quinolin-4-yl)- ureido)-4-methyl- 1-phenyl-1H-pyrazole-3- carboxamide 529.2 (M − H) 111

1-(6-(methoxy- methyl)-1-methyl- 2-(2,2,2-trifluoro- ethyl)-1,2,3,4-tetrahydroiso- quinolin-4-yl)-3- (4-methyl-3-(1- methyl-1H-imidazol-4-yl)- 1-phenyl-1H- pyrazol-5-yl)urea 568.2 (M + H) 112

1-(6-bromothio- chroman-4-yl)-3- (1′,4-dimethyl-1- phenyl-1H,1′H-[3,4′-bipyrazol]- 5-yl)urea 523.0 525.0 (M + H) 113

1-(6-bromo-1,1- dioxidothio- chroman-4-yl)- 3-(1′,4-dimethyl-1-phenyl-1H,1′H- [3,4′-bipyrazol]- 5-yl)urea 555.1 557.1 (M + H) 114

1-(6-bromoiso- thiochroman-4- yl)-3-(1′,4- dimethyl-1- phenyl-1H,1′H-[3,4′-bipyrazol]- 5-yl)urea 521.1 523.1 (M − H) 115

1-(6-bromo-2,2- dioxidoisothio- chroman-4-yl)- 3-(1′,4-dimethyl-1-phenyl-1H,1′H- [3,4′-bipyrazol]- 5-yl)urea 553.0 555.0 (M − H) 116

1-(1′,4-dimethyl- 1-phenyl-1H,1′H- [3,4′-bipyrazol]- 5-yl)-3-(1-oxo-2-(2,2,2-trifluoro- ethyl)-1,2,3,4- tetrahydroiso- quinolin-4-yl)urea522.1 (M − H)

Example 117

1-((1,2-trans)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-yl)urea

A mixture of CDI (61.1 mg, 0.226 mmol) (estimated 60% potent based onprevious experiments),4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-amine(Intermediate Y4, 60 mg, 0.226 mmol) and NEt₃ (99.3 μL, 0.712 mmol) werecombined in DMF (0.9 mL) and stirred at ambient temperature for 48hours. An aliquot of this solution containing5-(5-isocyanato-4-methyl-1-phenyl-1H-pyrazol-3-yl)-2-methylpyrimidine(approx. 0.22 M, 108 μL, 0.024 mmol) was diluted with DMF (0.2 mL),followed by addition oftrans-1-amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol(Intermediate X1, 5 mg, 0.026 mmol) and triethylamine (12 mg, 0.12mmol). After stirring at ambient temperature for 1 hour, the mixture wasdirectly purified by reverse phase chromatography (C18, 0-70%acetonitrile/water) to afford the title product as white solid (4.3 mg,37% yield). MS (apci) m/z=483.3 (M+H).

The compounds listed in Table 4 were prepared in a similar fashion asdescribed in Example 117, replacing4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-amine andtrans-1-amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol with theappropriate aminopyrazole and amine starting materials, respectively.

TABLE 4 Example MS (apci) # Structure Name m/z 118

1-(trans-2-hydroxy- 1,2,3,4-tetrahydro- naphthalen-1-yl)-3-(4-methyl-3-(2- methylpyrimidin-5- yl)-1-phenyl-1H- pyrazol-5-yl)urea455.2 (M + H) 119

1-(trans-2-hydroxy- 1,2,3,4-tetrahydro- naphthalen-1-yl)-3-(3-(2-methoxy- pyrimidin-5-yl)-4- methyl-1-phenyl- 1H-pyrazol-5-yl)urea471.2 (M + H) 120

5-(3-(trans-2- hydroxy-7- (methoxymethyl)- 4,4-dimethyl-1,2,3,4-tetrahydro- naphthalen-1-yl)- ureido)-N,4- dimethyl-1-phenyl-1H-pyrazole-3- carboxamide 490.3 (M − H) 121

1-(3,4-dimethyl-1- phenyl-1H-pyrazol- 5-yl)-3-(trans-2- hydroxy-1,2,3,4-tetrahydro- naphthalen-1-yl)urea 377.2 (M + H) 122

1-(trans-2-hydroxy- 4,4-dimethyl-1,2,3,4- tetrahydro-naphthalen-1-yl)-3- (4-methyl-3-((1- methylpiperidin-4- yl)methoxy)-1-phenyl-1H-pyrazol- 5-yl)urea 518.3 (M + H) 123

1-(trans-2-hydroxy- 1,2,3,4-tetrahydro- naphthalen-1-yl)-3-(4-methyl-3-((1- methylpiperidin-4- yl)methoxy)-1- phenyl-1H-pyrazol-5-yl)urea 490.3 (M + H) 124

5-(3-(trans-2- hydroxy-4,4- dimethyl-1,2,3,4- tetrahydro-naphthalen-1-yl)- ureido)-N,4- dimethyl-1-phenyl- 1H-pyrazole-3-carboxamide 448.2 (M + H) 125

5-(3-(trans-7-chloro- 2-hydroxy-4,4- dimethyl-1,2,3,4- tetrahydro-naphthalen-1-yl)- ureido)-N,4- dimethyl-1-phenyl- 1H-pyrazole-3-carboxamide 482.2 (M + H) 126

1-(3,4-dimethyl-1- phenyl-1H-pyrazol- 5-yl)-3-(trans-6- hydroxy-6,7,8,9-tetrahydro-5H- benzo[7]annulen- 5-yl)urea 391.2 (M + H) 127

1-(trans-6-hydroxy- 6,7,8,9-tetrahydro- 5H-benzo[7]annulen-5-yl)-3-(4-methyl-3- (2-methylpyrimidin- 5-yl)-1-phenyl-1H-pyrazol-5-yl)urea 469.2 (M + H) 128

1-(trans-6-hydroxy- 6,7,8,9-tetrahydro- 5H-benzo[7]annulen-5-yl)-3-(3-(2- methoxypyrimidin- 5-yl)-4-methyl-1- phenyl-1H-pyrazol-5-yl)urea 485.2 (M + H) 129

5-(3-(6-(methoxy- methyl)-1-methyl-2- (2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroiso- quinolin-4-yl)ureido)- N,4-dimethyl-1-phenyl-1H-pyrazole- 3-carboxamide 543.2 (M − H) 130

1-(4-methyl-3-(2- methylpyrimidin-5- yl)-1-phenyl-1H- pyrazol-5-yl)-3-(1-oxo-2-(2,2,2- trifluoroethyl)- 1,2,3,4-tetrahydro- isoquinolin-4-yl)-urea 534.2 (M − H) 131

1-(3,4-dimethyl-1- phenyl-1H-pyrazol- 5-yl)-3-(1-oxo-2-(2,2,2-trifluoroethyl)- 1,2,3,4-tetrahydro- isoquinolin-4-yl)urea 458.2(M + H)

Example 132

1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(4-methyl-1-phenyl-3-(quinuclidin-3-yloxy)-1H-pyrazol-5-yl)urea

To a solution of4-methyl-1-phenyl-3-(quinuclidin-3-yloxy)-1H-pyrazol-5-amine (0.051 g,0.17 mmol) in DriSolve DCM (1.7 mL) cooled in an ice-water bath wasadded triphosgene (0.0304 g, 0.10 mmol) followed by DIEA (0.089 mL, 0.51mmol). It was stirred at 0° C. for 1 hour, then(1R,2R)-1-amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol(Intermediate X2, 0.033 g, 0.17 mmol) was added in one portion. Thereaction mixture was allowed to warm to ambient temperature and wasstirred for 1 hour. The reaction mixture was concentrated and directlypurified by reverse phase chromatography (C18, 5 to 70% methanol/water)to yield the product as white solid (28.3 mg, 32% yield). MS (apci)m/z=516.3 (M+H).

Example 133

1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(4-methyl-3-(2-morpholinoethoxy)-1-phenyl-1H-pyrazol-5-yl)urea

The title product was prepared as described for Example 132, using4-methyl-3-(2-morpholinoethoxy)-1-phenyl-1H-pyrazol-5-amine(Intermediate P141, 0.025 g, 0.0827 mmol) instead of4-methyl-1-phenyl-3-(quinuclidin-3-yloxy)-1H-pyrazol-5-amine. The crudematerial was purified via reverse-phase chromatography (C18, 5 to 50%acetonitrile/water) to provide the title compound as white solid (24 mg,55% yield. MS (apci) m/z=520.3 (M+H).

Example 134

1-(3-(2-(dimethylamino)ethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)urea

The title product was prepared as described for Example 132, using3-(2-(dimethylamino)ethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-amine(Intermediate Y6, 0.030 g, 0.115 mmol) instead of4-methyl-1-phenyl-3-(quinuclidin-3-yloxy)-1H-pyrazol-5-amine. Theproduct was isolated via reverse-phase chromatography (C18, 5 to 50%acetonitrile/water) as white solid (10 mg, 18% yield. MS (apci)m/z=478.3 (M+H).

Example 135

1-((1R,2S)-2-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3-methoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Step 1. Synthesis of tert-butyl((1R,2S)-2-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate.Tert-butyl carbamate (363 mg, 3.10 mmol) was dissolved in 1-propanol (4mL) in a 20-mL scintillation vial equipped with a magnetic stir bar. Tothis solution was added a freshly prepared solution of sodium hydroxide(122 mg, 3.05 mmol) in water (7.5 mL) while stirring, followed byfreshly prepared tert-butyl hypochlorite (331 mg, 3.05 mmol, 0.35 mL). Asolution of the ligand (DHQD)2PHAL (38.9 mg, 0.0499 mmol) in 1-propanol(3.5 mL) was added to provide a clear colorless solution. The reactionvessel was immersed in a ambient-temperature water bath and stirred fora few minutes, and then 1,2-dihydronaphthalene (130 mg, 0.999 mmol) wasadded, followed by K2OsO4-2H2O (14.7 mg, 0.0399 mmol) in one portion.After 1 hour, the reaction mixture was diluted with EtOAc (7 mL) and thephases were separated. The aqueous phase was extracted with EtOAc (3×5mL). The combined organic layers were washed with water and brine, dried(Na₂SO₄), filtered and concentrated. The crude material was purifiedfirst by silica chromatography (10% acetone in hexanes) and then byreverse-phase chromatography (C18, 5 to 65% MeOH/water) to yield theproduct as colorless glassy solid (50 mg, 19% yield).

Step 2. Synthesis of1-((1R,2S)-2-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3-methoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea.Tert-butyl((1R,2S)-2-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate (25 mg,0.095 mmol) was treated with 1:1 v/v TFA/DCM (1 mL) at ambienttemperature for 1 hour, then concentrated. The residue was taken up inDCM (2 mL) and washed with 1N NaOH and brine (1 mL each), and theorganic phase was separated and concentrated. The residue was taken upin IPA (0.4 mL), followed by addition of phenyl(3-methoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)carbamate (intermediate 3,31 mg, 0.095 mmol) in one portion. The resulting milky suspension waswarmed up briefly with a heat gun to obtain a clear solution and thenheated at 50° C. for 3 hours, then at reflux for 1 hour. After coolingto ambient temperature, the reaction mixture was filtered, rinsed withice-cold IPA first followed by ether (0.5 mL each), yielding the productas white solid (10 mg, 27% yield). MS (apci) m/z=393.2 (M+H).

Example 136

1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(2′-(2,2,2-trifluoroethyl)-3′,4′-dihydro-2′H-spiro[cyclopropane-1,1′-isoquinolin]-4′-yl)ureatrifluoroacetate

Step A: Preparation of N-(2,2-dimethoxyethyl)-1-phenyl cyclopropanamine:A solution of 1-phenylcyclopropanamine (3.14 g, 23.6 mmol) in anhydrousDCM (100 mL) was treated with 2,2-dimethoxyacetaldehyde (4.09 g, 60% inwater, 23.6 mmol) followed by acetic acid (135 μL, 2.36 mmol) and MgSO₄(6.0 g). The mixture was stirred at ambient temperature for 16 hoursthen filtered, washed with a small amount of DCM and the filtratetreated with Na(OAc)₃BH (5.5 g, 25.9 mmol). After stirring at ambienttemperature for 16 hours, the mixture was treated with ice and 2N NaOHand then extracted with DCM (3×30 mL). The combined organic phases werewashed with brine (20 mL), dried over Na₂SO₄, filtered and concentrated.The residue was purified by silica column chromatography eluting with4:1 hexanes:EtOAc, to affordN-(2,2-dimethoxyethyl)-1-phenylcyclopropanamine (2.31 g, 44% yield) as apale yellow oil. MS (EI) m/z=220.05 (M−H).

Step B: Preparation ofN-(2,2-dimethoxyethyl)-1-phenyl-N-(2,2,2-trifluoroethyl)cyclopropanamineTo a solution of N-(2,2-dimethoxyethyl)-1-phenylcyclopropanamine (2.31g, 10.44 mmol) in anhydrous DMF (10 mL) was added2,2,2-trifluoroethyltriflate (3.76 mL, 26.1 mmol) followed by Et₃N (6.36mL, 36.5 mmol). The mixture was heated in a sealed vial at 45° C. for 16hours, then treated with 2,2,2-trifluoroethyltriflate (5 mL) and stirredat 65° C. for 6 hours. The cooled mixture was partitioned between water(50 mL) and EtOAc (50 mL) and the aqueous layer extracted with EtOAc(2×30 mL). The combined organic phases were washed with water (4×20 mL)and brine (20 mL) then dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by silica column chromatography eluting with 9:1 to4:1 hexanes:EtOAc, to affordN-(2,2-dimethoxyethyl)-1-phenyl-N-(2,2,2-trifluoroethyl)cyclopropanamine(934 mg, 29% yield) as a pale yellow oil. MS (apci) m/z=303.2 (M+H).

Step C: Preparation of2′-(2,2,2-trifluoroethyl)-3′,4′-dihydro-2′H-spiro[cyclopropane-1,1′-isoquinolin]-4′-ol:N-(2,2-dimethoxyethyl)-1-phenyl-N-(2,2,2-trifluoroethyl)cyclopropanamine(934 mg, 3.08 mmol) was treated with perchloric acid (3.72 mL, 61.6mmol) and stirred at ambient temperature for 3 hours. The mixture wastreated with ice and 2N NaOH, stirred for 1 hour then extracted with DCM(3×20 mL). The combined organic phases were washed with brine (10 mL),dried over Na₂SO₄, filtered and concentrated. The residue was purifiedby silica column chromatography eluting with 9:1 hexanes:EtOAc, toafford2′-(2,2,2-trifluoroethyl)-3′,4′-dihydro-2′H-spiro[cyclopropane-1,1′-isoquinolin]-4′-ol(328 mg, 41% yield) as a cream, crystalline solid. MS (apci) m/z=258.1(M+H).

Step D: Preparation of4′-chloro-2′-(2,2,2-trifluoroethyl)-3′,4′-dihydro-2′H-spiro[cyclopropane-1,1′-isoquinoline]:To a solution of2′-(2,2,2-trifluoroethyl)-3′,4′-dihydro-2′H-spiro[cyclopropane-1,1′-isoquinolin]-4′-ol(50 mg, 0.19 mmol) in anhydrous DCM (1 mL) at 0° C. was added mesylchloride (17 μL, 0.21 mmol) followed by DIEA (68 μL, 0.39 mmol). Themixture was stirred at ambient temperature for 2 hours then partitionedbetween water (10 mL) and DCM (10 mL). The aqueous layer was extractedwith DCM (2×5 mL) and the combined organic phases were washed with brine(10 mL), dried over Na₂SO₄, filtered and concentrated. The residue wasdissolved in DCM (10 mL) and concentrated to afford4′-chloro-2′-(2,2,2-trifluoroethyl)-3′,4′-dihydro-2′H-spiro[cyclopropane-1,1′-isoquinoline](50 mg, 93% yield) as a pale yellow oil. MS (EI) m/z=275.89 (M+H).

Step E: Preparation of4′-azido-2′-(2,2,2-trifluoroethyl)-3′,4′-dihydro-2′H-spiro[cyclopropane-1,1′-isoquinoline]:To a solution of4′-chloro-2′-(2,2,2-trifluoroethyl)-3′,4′-dihydro-2′H-spiro[cyclopropane-1,1′-isoquinoline](50 mg, 0.18 mmol) in anhydrous DMF (1 mL) was added sodium azide (24mg, 0.36 mmol). The mixture was stirred at 65° C. for 3 hours thencooled and partitioned between water (10 mL) and EtOAc (10 mL). Theaqueous layer was extracted with EtOAc (2×5 mL) and the combined organicphases were washed with water (4×5 mL) and brine (5 mL) then dried overNa₂SO₄, filtered and concentrated. The residue was purified by columnchromatography eluting with 9:1 hexanes:EtOAc, to afford4′-azido-2′-(2,2,2-trifluoroethyl)-3′,4′-dihydro-2′H-spiro[cyclopropane-1,1′-isoquinoline](19 mg, 37% yield) as a colorless oil. MS (apci) m/z=255.1 (M[−N2]+H).

Step F: Preparation of2′-(2,2,2-trifluoroethyl)-3′,4′-dihydro-2′H-spiro[cyclopropane-1,1′-isoquinolin]-4′-amine:A solution of4′-azido-2′-(2,2,2-trifluoroethyl)-3′,4′-dihydro-2′H-spiro[cyclopropane-1,1′-isoquinoline](19 mg, 0.067 mmol) in methanol (5 mL) was treated with 5% Pd/C (wet,Degussa type, 2 mg) and stirred under a hydrogen balloon atmosphere for3 hours. The mixture was filtered through GF paper and the filtrateconcentrated to afford2′-(2,2,2-trifluoroethyl)-3′,4′-dihydro-2′H-spiro[cyclopropane-1,1′-isoquinolin]-4′-amine(14 mg, 81% yield) as a colorless gum. MS (apci) m/z=257.1 (M+H).

Step G: Preparation of 1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(2′-(2,2,2-trifluoroethyl)-3′,4′-dihydro-2′H-spiro[cyclopropane-1,1′-isoquinolin]-4′-yl)urea2,2,2-trifluoroacetate: To a solution of2′-(2,2,2-trifluoroethyl)-3′,4′-dihydro-2′H-spiro[cyclopropane-1,1′-isoquinolin]-4′-amine(14 mg, 0.055 mmol) in anhydrous DCM (1 mL) was added phenyl(1′,4-dimethyl-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-yl)carbamate[Intermediate 13] (18 mg, 0.50 mmol) followed by DIEA (26 μL, 0.15mmol). The mixture was stirred at ambient temperature for 16 hours thenpartitioned between water (10 mL) and DCM (10 mL). The aqueous layer wasextracted with DCM (2×5 mL) and the combined organic phases were washedwith brine (10 mL), dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by silica column chromatography eluting with 2%MeOH/DCM, then by reverse-phase HPLC (5-95% ACN/water/0.1% TFA over 20minutes) to afford the title compound TFA salt (3.7 mg, 11% yield) as awhite solid. MS (apci) m/z=534.2 (M−H).

Example 137

1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((2′R,3′R)-2′-hydroxy-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-3′-yl)urea

To (2′R,3′R)-3′-amino-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2′-ol(Intermediate X9, 10.6 mg, 0.0605 mmol) were added iPrOH (0.6 mL) thenphenyl (1′,4-dimethyl-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-yl)carbamate(Intermediate 13, 22.6 mg, 0.0605 mmol). The reaction mixture was heatedto 70° C. for 15 minutes, then was allowed to cool slowly to ambienttemperature. The suspension was filtered, rinsed with Et2O (4×1 mL), andthe solid was collected to afford the product as a white solid (20.4 mg,74% yield). MS (apci) m/z=455.2 (M+H).

Example 138

1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((2'S,3'S)-2′-hydroxy-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-3′-yl)urea

To (2'S,3'S)-3′-amino-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2′-ol(Intermediate X10, 18.4 mg, 0.105 mmol) were added iPrOH (1 mL) thenphenyl (1′,4-dimethyl-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-yl)carbamate(Intermediate 13, 39.2 mg, 0.105 mmol). The reaction mixture was heatedto 70° C. for 15 minutes and then allowed to cool slowly to ambienttemperature. The suspension was filtered, rinsed with Et20 (4×1 mL), andthe solid was collected to afford the product as a white solid (37.4 mg,78% yield). MS (apci) m/z=455.2 (M+H).

Example 139

(R)-tert-butyl2-(((4-chloro-5-(3-((2′R,3′R)-2′-hydroxy-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-3′-yl)ureido)-1-phenyl-1H-pyrazol-3-yl)oxy)methyl)morpholine-4-carboxylateStep A: Preparation of (R)-tert-butyl2-(((5-((phenoxycarbonyl)amino)-1-phenyl-1H-pyrazol-3-yl)oxy)methyl)morpholine-4-carboxylate

To a solution of (R)-tert-butyl2-(((5-amino-1-phenyl-1H-pyrazol-3-yl)oxy)methyl)morpholine-4-carboxylate(Intermediate Y8, 200 mg, 0.534 mmol) in EtOAc (5 mL) was added aqueousNaOH (2M, 0.534 ml, 1.068 mmol) then phenyl chloroformate (100 μL,0.8012 mmol). The reaction mixture was stirred at ambient temperaturefor 23 hours and then transferred to separatory funnel with EtOAc (25mL). The phases were separated, and the organic phase was washed withH₂O (25 mL), brine (25 mL), dried (MgSO₄), filtered and concentrated toa thick syrup. Added hexanes (10 mL), sonicated, decanted hexanes, thendried under high vacuum to afford the product as a brown solid (242 mg,92% yield). MS (apci) m/z=495.2 (M+H).

Step B: Preparation of (R)-tert-butyl2-(((4-chloro-5-((phenoxycarbonyl)amino)-1-phenyl-1H-pyrazol-3-yl)oxy)methyl)morpholine-4-carboxylate

To a solution of (R)-tert-butyl2-(((5-((phenoxycarbonyl)amino)-1-phenyl-1H-pyrazol-3-yl)oxy)methyl)morpholine-4-carboxylate(242 mg, 0.489 mmol) in DCM (5 mL) were added NCS (85 mg, 0.636 mmol)and PPTS (12.3 mg, 0.049 mmol). The reaction mixture was stirred atambient temperature for 6 days, then was diluted with H₂O (10 mL),extracted with DCM (3×10 mL), and the combined organic phases were dried(MgSO₄), filtered, and concentrated. The crude oil was purified bysilica column chromatography, eluting with 0-30% acetone/hexanes, toafford the product as an orange solid (153 mg, 66% yield). MS (apci)m/z=429.1 (M-Boc).

Step C: Preparation of (R)-tert-butyl2-(((4-chloro-5-(3-((2′R,3′R)-2′-hydroxy-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-3′-yl)ureido)-1-phenyl-1H-pyrazol-3-yl)oxy)methyl)morpholine-4-carboxylate

To a solution of(2′R,3′R)-3′-amino-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-2′-ol(Intermediate X9, 24.2 mg, 0.138 mmol) in iPrOH (1.4 mL) was added(R)-tert-butyl2-(((4-chloro-5-((phenoxycarbonyl)amino)-1-phenyl-1H-pyrazol-3-yl)oxy)methyl)morpholine-4-carboxylate(73 mg, 0.138 mmol). The reaction mixture was stirred at ambienttemperature for 16 hours, then was diluted with DCM (2 mL) and purifiedby silica column chromatography, eluting with 0-10% MeOH/DCM, to affordthe product as an off-white solid (64 mg, 76% yield). MS (apci)m/z=510.2 (M-Boc).

Example 140

1-(4-chloro-3-((R)-morpholin-2-ylmethoxy)-1-phenyl-1H-pyrazol-5-yl)-3-((2′R,3′R)-2′-hydroxy-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-3′-yl)urea

To a suspension of (R)-tert-butyl2-(((4-chloro-5-(3-((2′R,3′R)-2′-hydroxy-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-3′-yl)ureido)-1-phenyl-1H-pyrazol-3-yl)oxy)methyl)morpholine-4-carboxylate(Example 139, 61 mg, 0.100 mmol) in iPrOH (0.2 mL) was added HCl (5-6Min iPrOH, 500 μL). The reaction mixture was stirred at ambienttemperature for 19 hours, then was diluted with saturated aqueous NaHCO₃(10 mL) and extracted with DCM (15 mL). The aqueous phase was dilutedwith H₂O (5 mL), then the aqueous phase was extracted with 10% MeOH/90%DCM (2×10 mL). The combined organic phases were dried (MgSO₄), filtered,concentrated, and dried under high vacuum to give the product as a whitesolid (44.7 mg, 88% yield). MS (apci) m/z=510.2 (M+H).

Example 141

1-(4-chloro-3-(((R)-4-methylmorpholin-2-yl)methoxy)-1-phenyl-1H-pyrazol-5-yl)-3-((2′R,3′R)-2′-hydroxy-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-3′-yl)urea

To a suspension of1-(4-chloro-3-((R)-morpholin-2-ylmethoxy)-1-phenyl-1H-pyrazol-5-yl)-3-((2′R,3′R)-2′-hydroxy-2′,3′-dihydrospiro[cyclopropane-1,1′-inden]-3′-yl)urea(Example 140, 25 mg, 0.049 mmol) in DCE (1 mL) were addedparaformaldehyde (3.5 mg, 0.117 mmol) then sodium triacetoxyborohydride(15.6 mg, 0.074 mmol). The reaction mixture was stirred at ambienttemperature for 16 hours, then at 50° C. for 1 hour. Additional sodiumtriacetoxyborohydride (8 mg, 0.038 mmol) was added and the reactionmixture was stirred at ambient temperature for 1 hour, then additionalsodium triacetoxyborohydride (8 mg, 0.038 mmol) was added and thereaction mixture was stirred at ambient temperature for 18 hours. Thereaction mixture was diluted with DCM (10 mL) and saturated aqueousNaHCO₃ (10 mL). The phases were separated and the aqueous phase wasextracted with 10% MeOH/90% DCM (2×10 mL). The combined organic phaseswere dried (MgSO₄), filtered, and concentrated. The crude product waspurified by silica column chromatography, eluting with 0-10% NH₃/MeOH inDCM, to afford the product as a white solid (14.3 mg, 56% yield). MS(apci) m/z=524.2 (M+H).

Example 142

1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(trans-2′-hydroxy-2′,3′-dihydrospiro[cyclobutane-1,1′-inden]-3′-yl)ureaStep A: Preparation of spiro[cyclobutane-1,1′-indene]

To a solution of 1H-indene (1.00 g, 8.609 mmol) and 1,3-dibromopropane(967 μL, 9.470 mmol) in DMSO (43 mL) was added KOtBu (2.125 g, 18.939mmol) in 4 portions over 5 min. The reaction mixture was stirred atambient temperature for 3 days, then was diluted with H₂O (50 mL) andextracted with Et₂O (3×50 mL). The combined organic phases were washedwith H₂O (50 mL), then brine (3×50 mL), then dried (MgSO₄), filtered,and concentrated. The crude oil was purified by silica columnchromatography, eluting with hexanes, to afford the product as acolorless oil (0.57 g, 42% yield).

Step B: Preparation of 1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(trans-2′-hydroxy-2′,3′-dihydrospiro[cyclobutane-1,1′-inden]-3′-yl)urea

Prepared according to the procedure of Example 55, Steps B-D, replacingspiro[cyclopropane-1,1′-indene] in Step B withspiro[cyclobutane-1,1′-indene]. The reaction mixture was purified bysilica column chromatography, eluting with 0-60% acetone/hexanes, toafford the product as a white solid (5.2 mg, 42% yield). MS (apci)m/z=469.2 (M+H).

Example 143

(R)-tert-butyl2-(((5-(3-(trans-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yl)oxy)methyl)morpholine-4-carboxylate

Step A: Preparation of (R)-tert-butyl2-(((4-methyl-5-((phenoxycarbonyl)amino)-1-phenyl-1H-pyrazol-3-yl)oxy)methyl)morpholine-4-carboxylate:To a solution of (R)-tert-butyl2-(((5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)oxy)methyl)morpholine-4-carboxylate(Intermediate Y7, 20 mg, 0.0515 mmol) in EtOAc (0.5 mL) were addedaqueous NaOH (2M, 51 μL, 0.103 mmol) then phenyl chloroformate (10 μL,0.077 mmol). The reaction mixture was stirred at ambient temperature for4 days, then transferred to separatory funnel with EtOAc (10 mL). Thephases were separated and the organic phase was washed with H₂O (10 mL),brine (10 mL), dried (MgSO₄), filtered, and concentrated to a thicksyrup. Added hexanes (10 mL), sonicated, decanted hexanes, then driedunder high vacuum to afford the product as an orange solid (20.5 mg, 78%yield). MS (apci) m/z=509.2 (M+H).

Step B: Preparation of (R)-tert-butyl2-(((5-(3-(trans-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yl)oxy)methyl)morpholine-4-carboxylate:To a solution of (R)-tert-butyl2-(((4-methyl-5-((phenoxycarbonyl)amino)-1-phenyl-1H-pyrazol-3-yl)oxy)methyl)morpholine-4-carboxylate(20 mg, 0.033 mmol) in iPrOH (0.5 mL) was addedtrans-1-amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol(Intermediate X1, 7.5 mg, 0.039 mmol). The reaction mixture was stirredat ambient temperature for 18 hours, then directly purified by silicacolumn chromatography, eluting with 0-10% MeOH/DCM, to afford theproduct as an off-white solid (13.7 mg, 53% yield). MS (apci) m/z=606.3(M+H)

Example 144

1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3-methoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Step A: Preparation of phenyl(3-methoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)carbamate: To a solution ofof 3-methoxy-4-methyl-1-phenyl-1H-pyrazol-5-amine (Intermediate 2, 646mg, 3.179 mmol) in EtOAc (32 mL) were added aqueous NaOH (2M, 3.18 mL,6.357 mmol) then phenyl chloroformate (0.5981 ml, 4.768 mmol). Thereaction mixture was stirred at ambient temperature for 17 hours andthen transferred to separatory funnel with EtOAc (25 mL). The phaseswere separated and the organic phase was washed with H₂O (25 mL), brine(25 mL), dried (MgSO₄), filtered, and concentrated to a thick syrup.Hexane (10 mL) was added, and the mixture was sonicated. The hexaneswere decanted and then dried under high vacuum to afford the product asa pale yellow solid (908 mg, 88% yield). MS (apci) m/z=324.1 (M+H).

Step B: Preparation of1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3-methoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea:To (1R,2R)-1-amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol(Intermediate X2, 198 mg, 1.04 mmol) were added iPrOH (5 mL) and phenyl(3-methoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)carbamate (335 mg, 1.04mmol). The reaction mixture was heated to 70° C. for 45 minutes, thencooled to ambient temperature. The suspension was filtered, rinsed withiPrOH (2×0.5 mL) then Et₂O (5×1 mL). The solid was collected, thenrecrystallized in iPrOH (2 mL), to afford the product as a white solid(95 mg, 22% yield). MS (apci) m/z=421.2 (M+H).

The examples in Table 5 were prepared according to the procedure ofExample 144, substituting the appropriate aminopyrazole intermediate inStep A.

TABLE 5 Ex. # Structure Name MS (apci) m/z 145

1-((1R,2R)-2-hydroxy-4,4- dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3- (1-methyl-3-phenyl-1H- pyrazol-5-yl)urea391.2 (M + H) 146

1-(3-ethoxy-4-methyl-1-phenyl- 1H-pyrazol-5-yl)-3-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4- tetrahydronaphthalen-1-yl)urea 435.3 (M +H) 147

1-((1R,2R)-2-hydroxy-4,4- dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3- (3-(2-methoxyethoxy)-4-methyl-1-phenyl-1H-pyrazol-5- yl)urea 465.3 (M + H)

Example 148

1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3-(2-hydroxyethyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Step A: Preparation of1-(3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)urea:Prepared according to the procedure of Example 144, replacing3-methoxy-4-methyl-1-phenyl-1H-pyrazol-5-amine in Step A with3-(2-(tert-butyldimethylsilyloxy)ethyl)-4-methyl-1-phenyl-1H-pyrazol-5-amine(Intermediate Y9). The reaction mixture was purified by silica columnchromatography, eluting with 0-60% acetone/hexanes, to afford theproduct as a pale yellow solid (26.8 mg, 47% yield). MS (apci) m/z=549.3(M+H).

Step B: Preparation of1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3-(2-hydroxyethyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea:To a solution of1-(3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)urea(26.8 mg, 0.0488 mmol) in EtOH (0.5 mL) was added HCl (5-6M in iPrOH,0.2 mL). The reaction mixture was stirred at ambient temperature for 2hours. The reaction mixture was concentrated, then diluted with Et₂O(3×3 mL) and concentrated after each addition, and dried under highvacuum to afford the product as a pale yellow solid (24.1 mg, 113%yield). MS (apci) m/z=435.3 (M+H).

Example 149

1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3-(2-hydroxyethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared according to the procedure of Example 148, replacing3-(2-(tert-butyldimethylsilyloxy)ethyl)-4-methyl-1-phenyl-1H-pyrazol-5-aminein Step A with 3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-amine (IntermediateP203), to afford the product as an off-white solid (33.7 mg, 106%yield). MS (apci) m/z=451.3 (M+H).

Example 150

1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(4-methyl-3-((R)-morpholin-2-ylmethoxy)-1-phenyl-1H-pyrazol-5-yl)urea

Step A: Preparation of (R)-tert-butyl2-(((5-(3-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yl)oxy)methyl)morpholine-4-carboxylate:Prepared according to the procedure of Example 143, replacingtrans-1-amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol in Step Bwith (1R,2R)-1-amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol(Intermediate X2), to afford the product as a pale yellow solid (134 mg,75% yield). MS (apci) m/z=606.3 (M+H).

Step B: Preparation of1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(4-methyl-3-((R)-morpholin-2-ylmethoxy)-1-phenyl-1H-pyrazol-5-yl)urea:To a solution of (R)-tert-butyl2-(((5-(3-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yl)oxy)methyl)morpholine-4-carboxylate(134 mg, 0.221 mmol) in iPrOH (3 mL) was added HCl (5-6M in iPrOH, 350μL). The reaction mixture was stirred at ambient temperature for 17hours, then additional HCl (5-6M in iPrOH, 1 mL) was added. The reactionmixture was stirred at ambient temperature for 24 hours, then dilutedwith saturated aqueous NaHCO₃ (25 mL) and extracted with DCM (3×25 mL).The combined organic phases were dried (MgSO₄), filtered, concentrated,and dried under high vacuum to give the product as a yellowish-tan solid(99 mg, 81% yield). MS (apci) m/z=506.3 (M+H).

Example 151

1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3-(((R)-4-isopropylmorpholin-2-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

To a suspension of1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(4-methyl-3-((R)-morpholin-2-ylmethoxy)-1-phenyl-1H-pyrazol-5-yl)urea(Example 150, 20 mg, 0.040 mmol) in DCE (0.5 mL) were added acetone (29μL, 0.396 mmol) then NaBH(OAc)₃ (13 mg, 0.059 mmol). The reactionmixture was stirred at ambient temperature for 19 hours, then additionalacetone (60 μL, 0.817 mmol) and NaBH(OAc)₃ (20 mg, 0.094 mmol). Thereaction mixture was stirred at ambient temperature for 2 hours, thendiluted with DCM (10 mL) and saturated aqueous NaHCO₃ (10 mL). Thephases were separated and the aqueous phase was extracted with 10%MeOH/90% DCM (2×10 mL). The combined organic phases were dried (MgSO₄),filtered, and concentrated. The crude product was purified by silicacolumn chromatography, eluting with 0-10% NH₃/MeOH in DCM, to afford theproduct as a white solid (16.3 mg, 75% yield). MS (apci) m/z=548.3(M+H).

Example 152

1-(trans-3′-hydroxy-3′,4′-dihydro-2′H-spiro[cyclopropane-1,1′-naphthalen]-4′-yl)-3-(3-methoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared according to the procedure of Example 144, replacing(1R,2R)-1-amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol in Step Bwithtrans-4′-amino-3′,4′-dihydro-2′H-spiro[cyclopropane-1,1′-naphthalen]-3′-ol(Intermediate X11). The reaction mixture was purified by silica columnchromatography, eluting with 0-10% NH₃/MeOH in DCM, to afford theproduct as a white solid (5.0 mg, 40% yield). MS (apci) m/z=419.2 (M+H).

The following examples in Table 6 were prepared according to theprocedure of Example 85, using the appropriate aminopyrazoleintermediate.

TABLE 6 Ex. # Structure Name MS (apci) m/z 153

1-((r-1,t-2,t-3)-2-hydroxy- 3-methoxy-4,4-dimethyl- 1,2,3,4-tetrahydronaphthalen-1- yl)-3-(3-methoxy-4- methyl-1-phenyl-1H-pyrazol-5-yl)urea 451.2 (M + H) 154

1-((r-1,t-2,t-3)-2-hydroxy- 3-methoxy-4,4-dimethyl- 1,2,3,4-tetrahydronaphthalen-1- yl)-3-(4-methyl-3-(1- methyl-6-oxo-1,6-dihydropyridin-3-yl)-1- phenyl-1H-pyrazol-5- yl)urea 528.2 (M + H) 155

1-((r-1,t2,t-3)-2-hydroxy- 3-methoxy-4,4-dimethyl- 1,2,3,4-tetrahydronaphthalen-1- yl)-3-(4-methyl-3-(2- methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5- yl)urea 513.2 (M + H)

Example 156

5-(3-((r-1,t-2,c-3)-2-hydroxy-3-methoxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)ureido)-N,4-dimethyl-1-phenyl-1H-pyrazole-3-carboxamide

Step A: Preparation of(r-1a,c-2,t-7b)-3,3-dimethyl-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxiren-2-ol:Stirred 1,1-dimethyl-1,2-dihydronaphthalen-2-ol (Example 85, Step C, 1.2g, 6.89 mmol) with 1,2-dichloroethane (15 mL) in an ice bath and addedsaturated aqueous NaHCO₃ (15 mL). 3-chlorobenzoperoxoic acid (2.55 g,10.3 mmol) was added and the reaction mixture was allowed to warm toambient temperature and stir overnight. The mixture was diluted withwater (30 mL) and DCM (30 mL). The phased were separated and the aqueousphase was extracted with DCM (30 mL). The combined organic layers werewashed with 2N NaOH (30 mL), dried (MgSO₄), filtered, and concentrated.The crude product was purified by silica gel column chromatography,eluting with 25% EtOAc/hexanes followed by 40% EtOAc/hexanes. Yield: 662mg (51%).

Step B: Preparation of(r-1a,c-2,t-7b)-2-methoxy-3,3-dimethyl-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirene:A round bottomed flask was charged with(r-1a,c-2,t-7b)-3,3-dimethyl-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxiren-2-ol(662 mg, 3.48 mmol) and anhydrous DMF (10 mL). The reaction mixture waschilled in an ice bath and sodium hydride (209 mg, 5.22 mmol; 60% inoil) was added in portions over 10 minutes under a stream of N₂. Thereaction mixture was stirred for 30 minutes in ice bath, and theniodomethane (433 μL, 6.96 mmol) was added. The flask was removed fromice bath and the reaction mixture was warmed to ambient temperature andstirred for 30 minutes. The reaction mixture was carefully quenched withsaturated aqueous NH₄Cl (10 mL), then diluted with H₂O (20 mL) andextracted with EtOAc (2×20 mL). The combined organic phases were washedwith water (20 mL), brine (20 mL), dried (MgSO₄), filtered, andconcentrated. The crude material was used in the next step withoutfurther purification (assuming theoretical yield. Yield: 777 g (109%).

Step C: Preparation of(r-1,t-2,c-3)-1-amino-3-methoxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol:The title compound was prepared from(r-1a,c-2,t-7b)-2-methoxy-3,3-dimethyl-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirene(711 mg, 3.48 mmol) according to the procedure described for Example 79,Step E. Yield: 315 mg (41%).

Step D: Preparation of5-(3-((r-1,t-2,c-3)-2-hydroxy-3-methoxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)ureido)-N,4-dimethyl-1-phenyl-1H-pyrazole-3-carboxamide:The title compound was prepared from(r-1,t-2,c-3)-1-amino-3-methoxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol(20 mg, 0.090 mmol) and5-amino-N,4-dimethyl-1-phenyl-1H-pyrazole-3-carboxamide (Intermediate10; 21 mg, 0.090 mmol) according to the procedure described for Example79, Step F. Yield: 4 mg (9%). MS m/z (APCI-pos) M+1=478.2.

The compounds in Table 7 were prepared according to the procedure ofExample 156, using the appropriate aminopyrazole intermediate.

TABLE 7 Ex. # Structure Name MS (apci) m/z 157

1-(1′,4-dimethyl-1- phenyl-1H,1′H-[3,4′- bipyrazol]-5-yl)-3-((r-1,t-2,c-3)-2-hydroxy-3- methoxy-4,4-dimethyl- 1,2,3,4-tetrahydronaphthalen- 1-yl)urea 501.2 (M + H) 158

1-((r-1,t-2,c-3)-2- hydroxy-3-methoxy- 4,4-dimethyl-1,2,3,4-tetrahydronaphthalen- 1-yl)-3-(4-methyl-3- ((1-methylpiperidin-4-yl)methoxy)-1-phenyl- 1H-pyrazol-5-yl)urea 548.3 (M + H)

Example 159

1-(trans-3-hydroxyspiro[chroman-2,1′-cyclobutan]-4-yl)-3-(3-methoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared according to the procedure of Example 144, replacing(1R,2R)-1-amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol in Step Bwith trans-4-aminospiro[chroman-2,1′-cyclobutan]-3-ol (Intermediate X12,10 mg, 0.049 mmol). The reaction mixture was purified by silica columnchromatography, eluting with 0-50% acetone/hexanes, to afford theproduct as a white solid (17.2 mg, 81% yield). MS (apci) m/z=435.3(M+H).

Example 160

1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(trans-3-hydroxyspiro[chroman-2,1′-cyclobutan]-4-yl)urea

Prepared according to the procedure of Example 159, replacing phenyl(3-methoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)carbamate with phenyl(1′,4-dimethyl-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-yl)carbamate(Intermediate 13, 18.2 mg, 0.049 mmol). The reaction mixture wasfiltered and rinsed Et₂O (3×0.5 mL) to afford the product as a whitesolid (17.1 mg, 72% yield). MS (apci) m/z=485.2 (M+H).

1. (canceled)
 2. A compound having the Formula 1-2:

or stereoisomers, tautomers, or pharmaceutically acceptable saltsthereof, wherein: X is O; Ring A is formula A-1

Y is H, halogen, or (1-3C alkoxy)(1-6C)alkyl; R^(a), R^(b) and R^(c) areH, halogen, (1-3C)alkoxy; B is NR¹, a bond CR^(d)R^(e); D is NR¹a bondor CR^(f)R^(g); E is NR¹, a bond or CR^(h)R^(i); F is CR^(j)R^(k);provided that the ring formed by B, D, E, and F together with the atomsto which they are attached contains at least five atoms; R¹ is(1-6C)alkyl [optionally substituted with one to five fluoros],(1-6C)cycloalkyl [optionally substituted with one to five fluoros],(1-3C alkoxy)(2-6C)alkyl [optionally substituted with one to fivefluoros], (1-6C)alkylC(═O)— or (1-6C alkoxy)C═O—; R^(d), R^(e), R^(f),R^(g), R^(h), R^(i), R^(j) and R^(k) are independently H, OH,(1-6C)alkyl [optionally substituted with one to five fluoros](1-3Calkoxy)(2-6C)alkyl [optionally substituted with one to five fluoros],(1-6C)alkoxy [optionally substituted with one to five fluoros], or (1-3Calkoxy)(2-6C)alkoxy [optionally substituted with one to five fluoros],or one of a pair of R^(d) and R^(e), or R^(f) and R^(g), or R^(h) andR^(i), or R^(j) and R^(k), together with the carbon atom to which theyare attached form a (3-6C)cycloalkyl ring, and wherein only one of R^(d)and R^(e) can be OH and neither is OH if B is connected to a heteroatom,and only one of R^(h) and R^(i) can be OH and neither is OH if E isconnected to a heteroatom; Ring C is formula C-1

R³ is Ar²; Ar² is phenyl; R⁴ is (1-6C)alkyl, hetCyc²(1-6C)alkoxy,hetAr⁴, aminocarbonyl, or hetAr⁵; hetCyc² is a 4-6 membered heterocyclicring having 1-2 ring heteroatoms independently selected from N and O andoptionally substituted with (1-6C)alkyl; hetAr⁴ is a 5-6 memberedheteroaryl ring having 1-3 ring heteroatoms independently selected fromN and O and optionally substituted with one or more substituentsindependently selected from (1-6C)alkyl and (1-6C)alkoxy; hetAr⁵ is:

where R^(z) is (1-3C)alkyl (optionally substituted with 1-3 fluoros),wherein said hetAr⁵ group is optionally further substituted with o(1-3C)alkyl; and R⁵ is (1-6C)alkyl.
 3. The compound according to claim2, wherein zero to four of R^(d), R^(e), R^(f), R^(g), R^(h), R^(i),R^(j) and R^(k) are independently H, OH, or (1-6C)alkyl [optionallysubstituted with one to five fluoros], or one of a pair of R^(d) andR^(e), or R^(f) and R^(g), or R^(h) and R^(i), or R³ and R^(k), togetherwith the carbon atom to which they are attached form a (3-6C)cycloalkylring.
 4. The compound according to claim 3, wherein zero to two ofR^(d), R^(e), R^(f), R^(g), R^(h), R^(i), R³ and R^(k) are independentlyH, OH, or (1-6C)alkyl [optionally substituted with one to five fluoros],or one of a pair of R^(d) and R^(e), or R^(f) and R^(g), or R^(h) andR^(i), or R³ and R^(k), together with the carbon atom to which they areattached form a (3-6C)cycloalkyl ring.
 5. The compound according toclaim 4, wherein zero to two of R^(d), R^(e), R^(f), R^(g), R^(h),R^(i), R³ and R^(k) are independently OH, methyl, methoxy, CH₃OCH₂CH₂O—,or cyclopropyl, or one of a pair of R^(d) and R^(e), or R^(f) and R^(g),or R^(h) and R^(i), or R³ and R^(k), together with the carbon atom towhich they are attached form a (3-6C)cycloalkylring.
 6. The compoundaccording to claim 5, wherein B is a bond or CR^(d)R^(e), D is a bond orCR^(f)R^(g), E is a bond or CR^(h)R^(i), and F is CR^(j)R^(k), providedthat the ring formed by B, D, E, and F together with the atoms to whichthey are attached contains at least five atoms.
 7. The compoundaccording to claim 5, wherein B is a bond or CR^(d)R^(e), D is NR¹, abond or CR^(f)R^(g), E is NR¹, a bond or CR^(h)R^(i), and F isCR^(j)R^(k), provided that the ring formed by B, D, E, and F togetherwith the atoms to which they are attached contains at least five atoms.8. The compound according to claim 5, wherein B is a NR¹, D is a bond orCR^(f)R^(g), E is a bond or CR^(h)R^(i), and F is CR³R^(k), providedthat the ring formed by B, D, E, and F together with the atoms to whichthey are attached contains at least five atoms.
 9. The compoundaccording to claim 5, wherein B is a bond or CR^(d)R^(e), D is NR¹, E isa bond or CR^(h)R^(i), and F is CR³R^(k), provided that the ring formedby B, D, E, and F together with the atoms to which they are attachedcontains at least five atoms.
 10. The compound according to claim 6,wherein Y is H.
 11. The compound according to claim 10, wherein R⁴ ishetAr⁴ or hetAr⁵.
 12. The compound according to claim 6, wherein Y is(1-3C alkoxy)(1-6C)alkyl.
 13. The compound according to claim 12,wherein R⁴ is hetAr⁴ or hetAr⁵.
 14. The compound according to claim 6,wherein Y is halogen.
 15. The compound according to claim 14, wherein R⁴is hetAr⁴ or hetAr⁵.
 16. The compound according to claim 7, wherein Y isH.
 17. The compound according to claim 16, wherein R⁴ is hetAr⁴ orhetAr⁵.
 18. The compound according to claim 7, wherein Y is (1-3Calkoxy)(1-6C)alkyl.
 19. The compound according to claim 18, wherein R⁴is hetAr⁴ or hetAr⁵.
 20. The compound according to claim 7 wherein Y ishalogen.
 21. The compound according to claim 20, wherein R⁴ is hetAr⁴ orhetAr⁵.
 22. The compound according to claim 8, wherein Y is H.
 23. Thecompound according to claim 22, wherein R⁴ is hetAr⁴ or hetAr⁵.
 24. Thecompound according to claim 8, wherein Y is (1-3C alkoxy)(1-6C)alkyl.25. The compound according to claim 24, wherein R⁴ is hetAr⁴ or hetAr⁵.26. The compound according to claim 8, wherein Y is halogen.
 27. Thecompound according to claim 26, wherein R⁴ is hetAr⁴ or hetAr⁵.
 28. Thecompound according to claim 9, wherein Y is H.
 29. The compoundaccording to claim 28, wherein R⁴ is hetAr⁴ or hetAr⁵.
 30. The compoundaccording to claim 9, wherein Y is (1-3C alkoxy)(1-6C)alkyl.
 31. Thecompound according to claim 30, wherein R⁴ is hetAr⁴ or hetAr⁵.
 32. Thecompound according to claim 9, wherein Y is halogen.
 33. The compoundaccording to claim 32, wherein R⁴ is hetAr⁴ or hetAr⁵.
 34. The compoundaccording to claim 2, selected from Ex. # Structure 1

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158

or a pharmaceutically acceptable salt thereof.
 35. A pharmaceuticalcomposition which comprises a compound of Formula I as defined in claim2 or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable diluent or carrier.